Health Evidence Review Commission's Genetics

October 16, 2014 10:00 AM

General Services Building Bachelor Butte Conference Room 1225 Ferry Street, Salem, Oregon

Section 1.0 Call to Order

AGENDA Genetics Advisory Council (GAC) October 16, 2014 10:00 am – 11:30 am Teleconference Public location: General Services Building, Bachelor Butte Conference Room, 1225 Ferry Street, Salem, Oregon

(All agenda items are subject to change and times listed are approximate)

# Time Item Presenter

1 10:00 AM Call to Order & Introductions Karen Kovak

2 10:05 AM Purpose of Meeting Ariel Smits

Ariel Smits 3 10:10 AM Review of New Genetics CPT Codes for 2015 Karen Kovak

5 11:20 AM Public Comment

6 11:30 AM Adjournment Karen Kovak

Section 2.0 New Codes 2015 Genetic Testing Codes Non-Prenatal 2015 Genetic Testing CPT Codes Recommendations Date: 10/16/14 Recommendation Impact of detecting a mutation Limitations & Comments CPT Descriptor Cover Don't Change Change Provide Provide Code Cover treatment health Prognosis genetic monitoring counseling 81288 MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; promoter methylation analysis 81410 Aortic dysfunction or dilation (eg, Marfan syndrome, Loeys Dietz syndrome, Ehler Danlos syndrome type IV, arterial tortuosity syndrome); genomic sequence analysis panel, must include sequencing of at least 9 genes, including FBN1, TGFBR1, TGFBR2, COL3A1, 81411 Aortic dysfunction or dilation (eg, Marfan syndrome, Loeys Dietz syndrome, Ehler Danlos syndrome type IV, arterial tortuosity syndrome); duplication/deletion analysis panel, must include analyses for TGFBR1, TGFBR2, MYH11, and COL3A1 81415 Exome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis 81416 Exome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis, each comparator exome (eg, parents, siblings) (List separately in addition to code for primary procedure)

81417 Exome (eg, unexplained constitutional or heritable disorder or syndrome); re-evaluation of previously obtained exome sequence (eg, updated knowledge or unrelated condition/syndrome)

1 2015 Genetic Testing Codes Non-Prenatal Recommendation Impact of detecting a mutation Limitations & Comments CPT Descriptor Cover Don't Change Change Provide Provide Code Cover treatment health Prognosis genetic monitoring counseling 81425 Genome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis 81426 Genome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis, each comparator genome (eg, parents, siblings) (List separately in addition to code for primary procedure)

81427 Genome (eg, unexplained constitutional or heritable disorder or syndrome); re-evaluation of previously obtained genome sequence (eg, updated knowledge or unrelated condition/syndrome) 81430 Hearing loss (eg, nonsyndromic hearing loss, Usher syndrome, Pendred syndrome); genomic sequence analysis panel, must include sequencing of at least 60 genes, including CDH23, CLRN1, GJB2, GPR98, MTRNR1, MYO7A, MYO15A, PCDH15, OTOF, SLC26A4, TMC1, TMPRSS3 81431 Hearing loss (eg, nonsyndromic hearing loss, Usher syndrome, Pendred syndrome); duplication/deletion analysis panel, must include copy number analyses for STRC and DFNB1 deletions in GJB2 and GJB6 genes

81435 Hereditary colon cancer syndromes (eg, Lynch syndrome, familial adenomatosis polyposis); genomic sequence analysis panel, must include analysis of at least 7 genes, including APC, CHEK2, MLH1, MSH2, MSH6, MUTYH, and PMS2

2 2015 Genetic Testing Codes Non-Prenatal Recommendation Impact of detecting a mutation Limitations & Comments CPT Descriptor Cover Don't Change Change Provide Provide Code Cover treatment health Prognosis genetic monitoring counseling 81436 Hereditary colon cancer syndromes (eg, Lynch syndrome, familial adenomatosis polyposis); duplication/deletion gene analysis panel, must include analysis of at least 8 genes, including APC, MLH1, MSH2, MSH6, PMS2, EPCAM, CHEK2, and MUTYH

81440 Nuclear encoded mitochondrial genes (eg, neurologic or myopathic phenotypes), genomic sequence panel, must include analysis of at least 100 genes, including BCS1L, C10orf2, COQ2, COX10, DGUOK, MPV17, OPA1, PDSS2, POLG, POLG2, RRM2B, SCO1, SCO2, SLC25A4, S

81460 Whole mitochondrial genome (eg, Leigh syndrome, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes [MELAS], myoclonic epilepsy with ragged-red fibers [MERFF], neuropathy, ataxia, and retinitis pigmentosa [NARP], Leber hereditary op

81465 Whole mitochondrial genome large deletion analysis panel (eg, Kearns-Sayre syndrome, chronic progressive external ophthalmoplegia), including heteroplasmy detection, if performed 81470 X-linked intellectual disability (XLID) (eg, syndromic and non-syndromic XLID); genomic sequence analysis panel, must include sequencing of at least 60 genes, including ARX, ATRX, CDKL5, FGD1, FMR1, HUWE1, IL1RAPL, KDM5C, L1CAM, MECP2, MED12, MID1, OCRL,

3 2015 Genetic Testing Codes Non-Prenatal Recommendation Impact of detecting a mutation Limitations & Comments CPT Descriptor Cover Don't Change Change Provide Provide Code Cover treatment health Prognosis genetic monitoring counseling 81471 X-linked intellectual disability (XLID) (eg, syndromic and non-syndromic XLID); duplication/deletion gene analysis, must include analysis of at least 60 genes, including ARX, ATRX, CDKL5, FGD1, FMR1, HUWE1, IL1RAPL, KDM5C, L1CAM, MECP2, MED12, MID1, OCRL,

4 2015 Genetic Testing CPT code review

81288, 81435, 81436 1) 81288: MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; promoter methylation analysis 2) 81436: Hereditary colon cancer syndromes (eg, Lynch syndrome, familial adenomatosis polyposis); duplication/deletion gene analysis panel, must include analysis of at least 7 genes, including APC, CHEK2, MLH1, MSH2, MSH6, MUTYH, and PMS2 3) Similar Prioritized List placements: a. Testing for Lynch syndrome (hereditary nonpolyposis colon cancer) (CPT 81292- 81300) with a guideline i. MLH1, MSH2, MSH6 individual gene tests (81292-81300) 1. Current MLH1 tests include full sequence analysis, known familial variants, and duplication/deletion variants (81292-81294) ii. PMS2 individual gene tests (81317-81319) 4) National Comprehensive Cancer Network (NCCN) 2014 screening guideline for colon cancer a. Recommends screening for MLH1, MSH2, MSH6, FMS2 and EPCAM for high risk family members 5) Recommendation a. Diagnostic List b. See recommended changes to the Non-Prenatal Genetic Testing Guideline

81410-81411 1) Aortic dysfunction or dilation (eg, Marfan syndrome, Loeys Dietz syndrome, Ehler Danlos syndrome type IV, arterial tortuosity syndrome); genomic sequence analysis pane 2) Used for diagnosing both symptomatic patients and asymptomatic family members 3) American College of Medical Genetics (2012)–evaluation of a patient with possible Marfan’s Syndrome a. Consider FBN1 gene sequencing b. Searching for mutations in FBN1continues to have a circumscribed role in the diagnosis of equivocal cases. Said differently, MFS remains, by and large, a clinical diagnosis. c. Does not address screening asymptomatic family members 4) American College of Cardiology/American Heart Association (2010) guidelines for diagnosis and management of patients with thoracic aortic disease a. Test for genes associated with aortic aneurysm and/or dissection in patients and family members (FBN1, TGFBR1, TGFBR2,COL3A1, ACTA2, MYH11)

1 2015 Genetic Testing CPT code review

b. Use test results to limit aortic imaging to relatives with the genetic mutation. (LOE: C) 1) Canadian Cardiovascular Society (2014) opinion a. We recommend clinical and genetic screening for suspected Marfan syndrome to clarify the nature of the disease and provide a basis for individual counselling (Strong Recommendation, High-Quality Evidence). b. Affects monitoring—recommend echocardiographic screening at diagnosis to measure aortic root and ascending aorta diameters, and repeated 6 months thereafter to determine rate of progression. If aortic diameters remain stable, annual imaging is recommended. (Strong Recommendation, High-Quality Evidence). 2) Recommendation: a. Diagnostic List

81425-81427 1) Exome testing 2) The human exome comprises only 1–2% of the whole genome, it is this portion that codes for proteins, and was thought to contain 85% of all pathogenic mutations causing Mendelian disorders. The exome can be sequenced in only 48 h at roughly a third of the cost, with far fewer data to store and analyse compared to whole genome testing 3) Cary Harding comments: a. May eliminate need for more expensive diagnostic studies such as muscle biopsy b. Usually parental DNA is analyzed for the variants discovered by exome sequencing of the proband without extra cost. Don't need whole exome of the parents. c. If any validation of an exome result is necessary, that should be done by another method rather than repeating an exome analysis 4) Recommendation:

2 2015 Genetic Testing CPT code review

81425-81427 1) Genome testing 2) Sequencing of an entire human genome to test for genetic mutations. The human genome can now be sequenced in 2 weeks for approximately £4000 (€4700, US$6200) in many laboratories. 3) Cary Harding comment: “not ready for clinical prime time” 4) Recommendation

81430-81431 1) 81430: Hearing loss (eg, nonsyndromic hearing loss, Usher syndrome, Pendred syndrome); genomic sequence analysis panel, must include sequencing of at least 60 genes, including CDH23, CLRN1, GJB2, GPR98, MTRNR1, MYO7A, MYO15A, PCDH15, OTOF, SLC26A4, TMC1, TMPRSS3 2) 81431: Hearing loss (eg, nonsyndromic hearing loss, Usher syndrome, Pendred syndrome); duplication/deletion analysis panel, must include copy number analyses for STRC and DFNB1 deletions in GJB2 and GJB6 genes 3) Similar code placement: a. GJB2 and GJB6 gene analysis assays for nonsyndromic hearing loss are on the diagnostic list (81252, 81253) 4) American College of Medical Genetics 2014, guideline for evaluation of hearing loss a. If nonsyndromic hearing loss is suspected, consider single-gene tests such as GJB2 and GJB6, gene panel tests, or NGS testing based on history and findings 5) Recommendation—single gene or panel?

81440 1) Nuclear encoded mitochondrial gene 2) Mutations of mitochondrial DNA can lead to a number of illnesses including exercise intolerance and Kearns-Sayre syndrome (KSS). Some evidence suggests that they might be major contributors to the aging process and age-associated pathologies. Recently a mutation in mtDNA has been used to help diagnose prostate cancer in patients with negative prostate biopsy. 3) Recommendation

81460, 81465 1) Whole mitochondrial genome 2) See 81440 above

3 2015 Genetic Testing CPT code review

3) Recommendation

81470, 81471 1) X-linked intellectual disability (XLID) (eg, syndromic and non-syndromic XLID); genomic sequence analysis panel 2) Refers to forms of intellectual disability which are specifically associated with X- linked recessive inheritance. As with most X-linked disorders, males are more heavily affected than females. Females with one affected X chromosome and one normal X chromosome tend to have milder symptoms. Unlike many other types of intellectual disability, the genetics of these conditions are relatively well understood. It has been estimated there are ~200 genes involved in this syndrome; of these ~100 have been identified. X-linked intellectual disability accounts for ~16% of all cases of intellectual disability in males. 3) The panel testing would include multiple of these known genes 4) Similar code coverage: a. CPT 81243, 81244 (Fragile X genetic testing) is covered with the following notation in the genetic testing guideline: i. “for individuals with intellectual disability/developmental delay. Although the yield of Fragile X is 3.5-10%, this is included because of additional reproductive implications.” 5) Recommendation: ??

4 GAC Recommended Changes to the Diagnostic Guideline D1, Non-Prenatal Genetic Testing Guideline October 16, 2014

Issues: 1) The Non-Prenatal Genetic Testing Algorithm has modifications suggested by the Genetics Advisory Committee. These suggestions have arisen out of the review of the 2015 CPT codes regarding specific genetic tests.

Recommendations: 1) Adopt the amended Diagnostic Guideline 1 as below

DIAGNOSTIC GUIDELINE D1, NON-PRENATAL GENETIC TESTING GUIDELINE Coverage of genetic testing in a non-prenatal setting shall be determined the algorithm shown in Figure C.1 unless otherwise specified below. A) Related to genetic testing for patients with breast/ovarian and colon/endometrial cancer suspected to be hereditary, or patients at increased risk to due to family history. 1) Services are provided according to the Comprehensive Cancer Network Guidelines. a) Lynch syndrome (hereditary colorectal and endometrial cancer) services (CPT 81288, 81292-81300, 81317-81319, 81435, 81436) and familial adenomatous polyposis (FAP) services (CPT 81201-81203) should be provided as defined by the NCCN Clinical Practice Guidelines in Oncology. Colorectal Cancer Screening. V.2.2104 V.1.2013 (5/13/13 5/19/14). www.nccn.org b) BRCA1/BRCA2 testing services (CPT 81211-81217) for women without a personal history of breast and/or ovarian cancer should be provided to high risk women as defined in Guideline Note 3 or as otherwise defined by the US Preventive Services Task Force. c) BRCA1/BRCA2 testing services (CPT 81211-81217) for women with a personal history of breast and/or ovarian cancer and for men with breast cancer should be provided according to the NCCN Clinical Practice Guidelines in Oncology. Genetic/Familial High- Risk Assessment: Breast and Ovarian. V.1.2011 (4/7/11). www.nccn.org d) PTEN (Cowden syndrome) services (CPT 81321-81323) should be provided as defined by the NCCN Clinical Practice Guidelines in Oncology. Colorectal Screening. V.1.2013 (5/13/13). www.nccn.org. 2) Genetic counseling should precede genetic testing for hereditary cancer. Very rarely, it may be appropriate for a genetic test to be performed prior to genetic counseling for a patient with cancer. If this is done, genetic counseling should be provided as soon as practical. a) Pre and post-test genetic counseling by the following providers should be covered. i) Medical Geneticist (M.D.) - Board Certified or Active Candidate Status from the American Board of Medical Genetics ii) Clinical Geneticist (Ph.D.) - Board Certified or Active Candidate Status from the American Board of Medical Genetics. iii) Genetic Counselor - Board Certified or Active Candidate Status from the American Board of Genetic Counseling, or Board Certified by the American Board of Medical Genetics. iv) Advance Practice Nurse in Genetics - Credential from the Genetic Nursing Credentialing Commission. 3) If the mutation in the family is known, only the test for that mutation is covered. For example, if a mutation for BRCA 1 has been identified in a family, a single site mutation analysis for that mutation is covered (CPT 81215), while a full sequence BRCA 1 and 2 (CPT 81211) analyses is not. There is one exception, for individuals of Ashkenazi Jewish ancestry with a known mutation in the family, the panel for Ashkenazi Jewish BRCA mutations is covered (CPT 81212). 4) Costs for rush genetic testing for hereditary breast/ovarian and colon/endometrial cancer is not covered. B) Related to diagnostic evaluation of individuals with intellectual disability (defined as a full scale or verbal IQ < 70 in an individual > age 5), developmental delay (defined as a cognitive index <70 on a standardized test appropriate for children < 5 years of age), Autism Spectrum Disorder, or multiple congenital anomalies:

Non Prenatal Genetic Testing Algorithm, Page 1 GAC Recommended Changes to the Diagnostic Guideline D1, Non-Prenatal Genetic Testing Guideline October 16, 2014

1) CPT 81228, Cytogenomic constitutional microarray analysis for copy number variants for chromosomal abnormalities: Cover for diagnostic evaluation of individuals with intellectual disability/developmental delay; multiple congenital anomalies; or, Autism Spectrum Disorder accompanied by at least one of the following: dysmorphic features including macro or microcephaly, congenital anomalies, or intellectual disability/developmental delay in addition to those required to diagnose Autism Spectrum Disorder. In 2012, this test may also be billed using one of CPT 88384-88386, or stacking CPTs 83890-83915. 2) CPT 81229, Cytogenomic constitutional microarray analysis for copy number variants for chromosomal abnormalities; plus cytogenetic constitutional microarray analysis for single nucleotide polymorphism (SNP) variants for chromosomal abnormalities: Cover for diagnostic evaluation of individuals with intellectual disability/developmental delay; multiple congenital anomalies; or, Autism Spectrum Disorder accompanied by at least one of the following: dysmorphic features including macro or microcephaly, congenital anomalies, or intellectual disability/developmental delay in addition to those required to diagnose Autism Spectrum Disorder; only if (a) consanguinity and recessive disease is suspected, or (b) uniparental disomy is suspected, or (c) another mechanism is suspected that is not detected by the copy number variant test alone. In 2012, this test may also be billed using one of CPT 88384- 88386, or stacking CPTs 83890-83915. 3) CPT 81243, 81244, Fragile X genetic testing is covered for individuals with intellectual disability/developmental delay. Although the yield of Fragile X is 3.5-10%, this is included because of additional reproductive implications. 4) A visit with the appropriate specialist (often genetics, developmental pediatrics, or child neurology), including physical exam, medical history, and family history is covered. Physical exam, medical history, and family history by the appropriate specialist, prior to any genetic testing is often the most cost-effective strategy and is encouraged. C) Related to other tests with specific CPT codes: 1) The following tests are not covered: a) CPT 81225, CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *5, *6) b) CPT 81226, CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN). c) CPT 81227, CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *5, *6) d) CPT 81287, MGMT (O-6-methylguanine-DNA methyltransferase) (eg, glioblastoma multiforme), methylation analysis e) CPT 81291, MTHFR (5,10-methylenetetrahydrofolate reductase) (eg, hereditary hypercoagulability) gene analysis, common variants (eg, 677T, 1298C) f) CPT 81330, SMPD1(sphingomyelin phosphodiesterase 1, acid lysosomal) (eg, Niemann- Pick disease, Type A) gene analysis, common variants (eg, R496L, L302P, fsP330) g) CPT 81350, UGT1A1 (UDP glucuronosyltransferase 1 family, polypeptide A1) (eg, irinotecan metabolism), gene analysis, common variants (eg, *28, *36, *37) h) CPT 81355, VKORC1 (vitamin K epoxide reductase complex, subunit 1) (eg, warfarin metabolism), gene analysis, common variants (eg, -1639/3673) i) CPT 81504, Oncology (tissue of origin), microarray gene expression profiling of > 2000 genes, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as tissue similarity scores 2) The following tests are covered only if they meet the criteria for the Non-Prenatal Genetic Testing Algorithm AND the specified situations: a) CPT 81205, BCKDHB (branched-chain keto acid dehydrogenase E1, beta polypeptide) (eg, Maple syrup urine disease) gene analysis, common variants (eg, R183P, G278S, E422X): Cover only when the newborn screening test is abnormal and serum amino acids are normal b) Diagnostic testing for cystic fibrosis (CF) i) CFTR, cystic fibrosis transmembrane conductance regulator tests. CPT 81220, 81223, 81222: For infants with a positive newborn screen for cystic fibrosis or who

Non Prenatal Genetic Testing Algorithm, Page 2 GAC Recommended Changes to the Diagnostic Guideline D1, Non-Prenatal Genetic Testing Guideline October 16, 2014

are symptomatic for cystic fibrosis, or for clients that have previously been diagnosed with cystic fibrosis but have not had genetic testing, CFTR gene analysis of a panel containing at least the mutations recommended by the American College of Medical Genetics* (CPT 81220) is covered. If two mutations are not identified, CFTR full gene sequencing (CPT 81223) is covered. If two mutations are still not identified, duplication/deletion testing (CPT 81222) is covered. These tests may be ordered as reflex testing on the same specimen. c) Carrier testing for cystic fibrosis i) CFTR gene analysis of a panel containing at least the mutations recommended by the American College of Medical Genetics* (CPT 81220) is covered. d) CPT 81240. F2 (prothrombin, coagulation factor II) (eg, hereditary hypercoagulability) gene analysis, 20210G>A variant: Factor 2 20210G>A testing should not be covered for adults with idiopathic venous thromoboembolism; for asymptomatic family members of patients with venous thromboembolism and a Factor V Leiden or Prothrombin 20210G>A mutation; or for determining the etiology of recurrent fetal loss or placental abruption. e) CPT 81241. F5 (coagulation Factor V) (eg, hereditary hypercoagulability) gene analysis, Leiden variant: Factor V Leiden testing should not be covered for: adults with idiopathic venous thromoboembolism; for asymptomatic family members of patients with venous thromboembolism and a Factor V Leiden or Prothrombin 20210G>A mutation; or for determining the etiology of recurrent fetal loss or placental abruption. f) CPT 81256, HFE (hemochromatosis) (eg, hereditary hemochromatosis) gene analysis, common variants (eg, C282Y, H63D): Covered for diagnostic testing of patients with elevated transferrin saturation or ferritin levels. Covered for predictive testing ONLY when a first degree family member has treatable iron overload from HFE. g) CPT 81332 SERPINA1 (serpin peptidase inhibitor, clade A, alpha-1 antiproteinase, antitrypsin, member 1) (eg, alpha-1-antitrypsin deficiency), gene analysis, common variants (eg, *S and *Z): The alpha-1-antitrypsin protein level should be the first line test for a suspected diagnosis of AAT deficiency in symptomatic individuals with unexplained liver disease or obstructive lung disease that is not asthma or in a middle age individual with unexplained dyspnea. Generic testing or the anpha-1 phenotype test is appropriate is the protein test is abnormal or borderline. The genetic test is appropriate for siblings of people with AAT deficiency regardless of the AAT protein test results. 3) Do not cover a more expensive genetic test (generally one with a wider scope or more detailed testing) if a cheaper (smaller scope) test is available and has, in this clinical context, a substantially similar sensitivity. For example, do not cover CFTR gene sequencing as the first test in a person of Northern European Caucasian ancestry because the gene panels are less expensive and provide substantially similar sensitivity in that context.

Non Prenatal Genetic Testing Algorithm, Page 3 ©American College of Medical Genetics ACMG practice guidelines

Evaluation of the adolescent or adult with some features of Marfan syndrome

Reed E. Pyeritz, MD, PhD;1 for the Professional Practice and Guidelines Committee, ACMG

Disclaimer: ACMG standards and guidelines are designed primarily as an educational resource for medical geneticists and other health care providers to help them provide quality medical genetic services. Adherence to these standards and guidelines does not necessarily ensure a successful medical outcome. These standards and guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the geneticists should apply their own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the patient’s record the rationale for any significant deviation from these standards and guidelines.

Individuals who are suspected of having Marfan syndrome are often of these individuals. This practice guideline providesguidance for the referred to a medical geneticist for further evaluation and diagnosis. approach to this cadre of individuals. However, there are a number of conditions that share physical mani- Genet Med 2012:14(1):171–177 festations with those of Marfan syndrome; therefore, an approach to diagnosis and evaluation is crucial to the proper long-term follow-up Key Words: aortic aneurysm; aortic dissection; fibrillin; Loeys–Dietz syndrome; marfanoid

INTRODUCTION • Congenital contractural arachnodactyly (CCA) (121050) A common reason for referral to cardiologists and medical • MASS phenotype (604308) geneticists is the tall, lanky individual who wants clearance for • Familial arterial tortuosity syndrome (208050) physical activities or who has vague complaints of discomfort • Familial mitral valve prolapse (MVP) (157700) in the back, chest, or joints. Obviously, concern for Marfan • Familial ectopia lentis (129600) syndrome (MFS) is appropriate, but frequently the diagnosis • Bicuspid aortic valve sequence (109730) cannot be established by the original “Ghent Criteria.”1 The spe- • Familial tall stature cialist often wonders whether or how to label such an individual, • Familial pectus excavatum (169300) whether further testing (such as computed tomography (CT) of • Familial scoliosis (181800) the spine) or molecular genetic testing is necessary, and whether • Stickler syndrome (108300) to recommend follow-up evaluation. New diagnostic criteria for MFS have been published recently.2 A practice guideline that Diagnostic criteria for these related disorders are based entirely addresses these issues in the context of the new criteria will assist on expert opinion, but rarely have groups of experts collabo- a variety of clinicians in dealing more appropriately with such rated on refining their ideas.1,3 The entire field suffers from the patients and reduce instances of overly restricting people who lack of any systematic attempt to apply rigorous methodology do not have MFS or inappropriately reassuring those who do. to categorization. The focus of what follows is the evaluation for The following list of disorders (with OMIM numbers in paren- the MFS. Comments about the other disorders are included as theses) presents considerable diagnostic challenges because of an appendix. shared features, overlapping phenotypes, similar inheritance Medical geneticists, cardiologists, and sports medicine phy- patterns, and, at least for some, causation by mutations in the sicians, among others, are frequently consulted about tall, thin same gene, FBN1. children and adolescents out of concern for MFS. The main reason that primary-care providers are interested in ruling • MFS (154700) MFS in or out is the risk of progressive aortic dilatation and • Ehlers–Danlos syndrome, hypermobile type (EDS) (130020) aortic dissection, particularly related to physical activity. In this • Familial thoracic aortic aneurysm and dissection (reviewed regard, if the echocardiogram shows an aortic root dimension in 607086) within the normal range for body surface area,4 in almost all • Loeys–Dietz syndrome (LDS) and other disorders of TGFβ of the disorders to be considered, the risk of aortic dissection receptors (reviewed in 609192) is very low. The one exception is LDS5 and other phenotypes

1Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Correspondence: Reed E. Pyeritz ([email protected]) Submitted 24 October 2011; accepted 25 October 2011; advance online publication 5 January 2012. doi:10.1038/gim.2011.48

Genetics in medicine | Volume 14 | Number 1 | January 2012 171 acmg practice guidelines PYERITZ | Marfanoid evaluation associated with mutations in TGFBR1 and TGFBR2,6 in some Bayesian sense. For example, lumbosacral dural ectasia occurs of which both the aorta and its major branches dissect in the in very few conditions besides MFS and LDS and almost never absence of much, if any, dilatation. Thus, the echocardiogram in the absence of some systemic disorder. This prompted the is an essential test whenever any of these conditions is con- inclusion of dural ectasia as a “major criterion” for the diagno- sidered seriously and whenever concerns about modulating sis of MFS in the Ghent scheme.1 Similar reasoning was used physical activity are raised. Likewise, a slit-lamp examination, to so distinguish ectopia lentis, aortic dissection, and aortic with the pupils fully dilated, is essential to exclude ectopia dilatation. But it is important to emphasize again that these lentis; when MFS is seriously suspected, this test should be decisions were based on expert opinion and are just beginning performed by an ophthalmologist comfortable with the ocular to be subjected to formal scrutiny. If the diagnosis of MFS is features of MFS. clear in a patient who has no back or radicular pain, then Because all of the conditions listed above (except arterial there is almost no need to image the lower spine. On the other tortuosity syndrome, which is recessive) can be inherited as hand, if the diagnosis of MFS hangs on whether dural ectasia autosomal dominant traits, the family history is a crucial com- is present, then the effort, expense, and radiation (if a CT scan ponent of any diagnostic matrix. Historical information may is done) of imaging are warranted. The severity of dural ecta- suffice, but usually more detail is needed in the form of medi- sia is clearly age dependent, but no cross-sectional survey of a cal and autopsy records. Frequently, a grandparent dies of an pediatric population has been performed to determine when “aneurysm” and the family does not know what vessel or what radiographic features appear. In the new diagnostic criteria region of the aorta was involved. More so in the past than now, for MFS, the presence or absence of dural ectasia has been a relative who died of an ascending aortic dissection and had a reduced in importance. postmortem examination that showed “cystic medical necrosis” Some of the diagnoses are ones of exclusion. For example, was automatically said to have had MFS, even in the absence of a family history of aortic aneurysms and mild thoracic-cage any other physical features of that condition. Personally exam- abnormalities, with no one meeting criteria for MFS, warrants ining the sibs and parents of a child in whom MFS is suspected a label of familial aortic aneurysm (although that implies little is at least as important as obtaining a complete family history. about etiology). Likewise, a family history of MVP and mild Many of the helpful diagnostic features, such as scoliosis, striae joint hypermobility, in the absence of features of MASS such atrophicae, disproportionate stature, MVP, and aortic root dila- as striae, thoracic-cage abnormalities, and myopia, warrants a tation are clinically silent and may not be apparent to the rela- label of familial MVP. Familial pectus, familial tall stature, and tive and those close to him or her. familial ectopia lentis fall into this group. Occasionally, long- Almost all of the conditions listed above are “syndromes,” in term follow-up of patients or introduction of relatives with a that multiple features are required to establish the diagnosis. wider spectrum of features may prompt reevaluation of the For those conditions caused by a mutation in a single gene, initial diagnosis. This has happened rather often with familial the syndromic features are pleiotropic manifestations of the ectopia lentis due to mutations in FBN1. mutation and the pathogenetic mechanisms that derive from Because echocardiography is an expensive, if benign, test, it. However, a number of important caveats affect this inter- physicians often wonder whether to rescreen and at what pretation. First, virtually all of the features are age dependent; interval. Certainly in MFS, a maximum interval is annually; when examining a young relative, usually fewer features will be the larger the aortic root diameter, the more frequently the evident than in older relatives. Second, all genetic syndromes test should be performed. This holds for familial aortic aneu- show variable expression beyond age dependency, for rea- rysm, bicuspid aortic valve with aneurysm, and LDS. For the sons that are poorly understood. Third, many of the features tall, lanky adolescent with flat feet and myopia, if the fam- of these conditions also occur “sporadically” in the general ily history is unremarkable and the initial echocardiogram population for both genetic and nongenetic reasons. Examples is completely normal, the study might be repeated only if are nearsightedness, tall stature, pectus excavatum, scoliosis, cardiovascular symptoms arise. A great many patients fall joint hypermobility, and MVP. Fourth, many of these same fea- somewhere in between, and repeating an echocardiogram tures are more likely to occur among relatives because of poly- every 2 to 3 years, or whenever a major increase in physical genic contributions to pathogenesis. Occasional families will exertion is planned, seems reasonable. Interestingly, patients show such frequent occurrence of one of these features that followed by cardiologists tend to have echocardiograms more Mendelian inheritance is inferred; this led to some of the diag- frequently. noses listed above, although with rare exceptions the causative Anyone with moderate or severe aortic root dilation and/or a locus has not been identified. Examples are familial forms of TGFBR1 or -2 mutation should be taught the signs and symp- pectus excavatum, scoliosis, tall stature, and what the rheuma- toms of aortic dissection and should consider wearing a medi- tologists term “familial benign joint hypermobility,” which is cal alert bracelet. distinguished from forms of EDS by an absence of involvement of the skin. EVALUATION FOR MFS The frequency of specific features in the general popula- MFS is characterized by autosomal dominant inheritance of tion contributes to their importance as diagnostic criteria in a features in the skeletal, ocular, cardiovascular, and pulmonary

172 Volume 14 | Number 1 | January 2012 | Genetics in medicine Marfanoid evaluation | PYERITZ acmg practice guidelines systems, along with muscular and adipose hypoplasia, dural Reduced upper-to-lower segment ratio AND increased arm/ ectasia, and hernias.7 As individuals with MFS live longer height AND no severe scoliosis = 1 with aggressive and prophylactic management of their car- Scoliosis or thoracolumbar kyphosis = 1 diovascular disease, additional features are emerging, such as Reduced elbow extension = 1 renal and hepatic cysts.8 Because about one-third of patients Facial features (three of five including dolichocephaly, enoph have parents unaffected by MFS, more features are required thalmos, downslanting palpebral fissures, malar hypoplasia, in them to be certain of the diagnosis. Mutations in FBN1, and retrognathia) = 1 the gene that encodes the large glycoprotein, fibrillin-1, Skin striae = 1 cause MFS, but also cause many of the related conditions. Myopia >3 diopters = 1 Conversely, conditions that have been confused with MFS, Mitral valve prolapse (all types) = 1 such as CCA and LDS, are due to mutations in genes that Maximum total: 20 points; score of 7 or more indicates encode either related proteins (e.g., fibrillin-2) or proteins systemic involvement involved in pathogenesis of common features (e.g., TGFβ receptors). There is no case of classic, bona fide MFS due to Diagnostic evaluation mutations in a gene other than FBN1. However, current clini- 1. Physical exam cal molecular testing of FBN1 successfully detects mutations 2. Family history in such unequivocal patients in only about 90–95% of cases.9 3. Echocardiogram For all of these reasons, searching for mutations in FBN1 4. Dilated eye exam continues to have a circumscribed role in the diagnosis of 5. Consider CT or magnetic resonance imaging for evidence equivocal cases. Said differently, MFS remains, by and large, of lumbosacral dural ectasia and protrusion acetabulae a clinical diagnosis. 6. Consider FBN1 gene sequencing

Diagnostic criteria Management If there is no family history of MFS, then the subject has the Cardiovascular: (recommend management by a skilled condition under any of the following four situations: cardiologist) A. Aortic root dilation and/or diagnostic criteria met for MFS: A dilated aortic root (defined as greater than or equal to two Annual echocardiogram for root diameter <4.5 cm in an standard deviations above the mean for age, sex, and body adult and rate of increase <0.5 cm/year surface area, i.e., a Z-score of > +2) and ectopia lentis β-Blocker therapy.10 A randomized controlled trial of losartan A dilated aortic root and a mutation in FBN1 that is clearly versus atenolol is under way, but the results are potentially pathologic not available until 2013–14.11 The finalN of 604 subjects was A dilated aortic root and multiple systemic features (see reached at the end of January 2011. below) or Echocardiogram every 6 months if diameter is >2 SD in an Ectopia lentis and a mutation in FBN1 that has previously adult or rate of increase in size is >0.5 cm/year been associated with aortic disease Surgical repair for measurements >4.5 cm, rate of increase in size >1 cm/year, or progressive aortic regurgitation If there is a positive family history of MFS (independently Magnetic resonance angiography or CT of the entire aorta ascertained with these criteria), then the subject has the condi- starting in young adulthood. Repeat annually if there is tion under any of the following three situations: a history of aortic root replacement or dissection, less frequently if not Ectopia lentis Multiple systemic features (see below) or B. Normal aortic root size with systemic involvement of A dilated aortic root (if over 20 years, greater than two another system with a positive family/genetic history: standard deviations; if younger than 20, greater than three Annual echocardiogram standard deviations) C. Normal aortic root size with systemic involvement with a The scoring system for systemic features involves the following: negative family/genetic history: Repeat echocardiogram every 2 to 3 years until adult height Wrist AND thumb sign = 3 (wrist OR thumb sign = 1) is reached. Then repeat if symptomatic or when a major Pectus carinatum deformity = 2 (pectus excavatum or chest increase in physical activity is planned. The diameter of asymmetry = 1) the aortic root is slightly larger in men than women of the Hindfoot deformity = 2 (plain pes planus = 1) same body size and, in both sexes, increases very slightly Pneumothorax = 2 and gradually in normal individuals with age, but should not Dural ectasia = 2 exceed the general upper limit of normal of 40–42 mm, even Protrusio acetabuli = 2 in tall individuals.

Genetics in medicine | Volume 14 | Number 1 | January 2012 173 acmg practice guidelines PYERITZ | Marfanoid evaluation

APPENDIX Diagnostic evaluation 1. Physical exam 2. Family history EDS HYPERMOBILE TYPE 3. Echocardiogram to evaluate for aortic root dilatation Joint hypermobility in this condition may mimic that in MFS. 4. Dilated eye exam (to exclude MFS) The skin may be mildly hyperextensible whereas it rarely is in MFS. Aortic root dilation, usually mild, occurs in one- Management quarter to one-third of individuals with EDS classic and Cardiovascular: (recommend management by a skilled hypermobility types.12 There is not thought to be a risk of dis- cardiologist) section without significant aortic root dilatation. Long-term A. Normal aortic root size: prognosis is not known. Other features include joint laxity, Repeat echocardiogram every 2–3 years until adult height easy bruising, functional bowel disorders, osteoporosis, and reached. If no dilatation present, repeat echocardiogram if chronic pain. cardiovascular symptoms develop or when a major increase in physical activity is planned. If dilatation present, follow as Diagnostic criteria described in the next section. Diagnosis is based on clinical evaluation and family history. A small subset of individuals with the hypermobile form of B. Aortic root dilation: EDS have an insertion or deletion in the TNXB gene. Echocardiogram every 6 months if diameter is >4.5 cm in an adult or rate of increase in size is >0.5 cm/year. Annual Major diagnostic criteria13 echocardiogram for root diameter <4.5 cm in an adult and All of the following criteria should be met to establish a diagno- rate of increase is <0.5 cm/year sis of EDS, hypermobility type: C. Bone Density: 1. Joint hypermobility confirmed by a score of 5 or more on Encourage calcium and vitamin D supplementation the 9-point Beighton scale:14 Low-impact weight-bearing exercise Passive dorsiflexion of each fifth finger >90 degrees Order DXA scan for height loss greater than one inch (1 point each side) Passive apposition of each thumb to the flexor surface D. Gastrointestinal: of the forearm (1 point each side) Gastritis and reflux may require a proton pump inhibitor, Hyperextension of each elbow >10 degrees (1 point H-2 blocker, and sucralfate. each side) Delayed gastric emptying may require a promotility agent Hyperextension of each knee >10 degrees (1 point Irritable bowel is treated with antispasmodics, antidiarrheals, each side) and laxatives as needed Place palms flat on the floor when bending over with knees fully extended (1 point) E. Musculoskeletal: 2. Soft or velvety skin with normal or slightly increased Low-resistance exercise is recommended to improve joint extensibility stability by increasing muscle tone. Physical therapy for 3. Absence of skin or soft tissue fragility (suggestive of other myofascial release is often necessary to facilitate participation EDS subtypes) in low-resistance exercise. A pain management specialist is a crucial participant in the care of a patient with EDS Minor diagnostic criteria hypermobile type with chronic pain. Due to a general decrease These criteria are supportive but not sufficient to establish the in the degree of stabilization and pain reduction and the diagnosis. duration of improvement as compared with those without EDS hypermobile type, orthopedic surgery should be delayed, 1. Autosomal dominant family history of similar features if possible, in favor of physical therapy and bracing. without skin abnormalities Vitamin C is a cofactor for cross-linking of collagen fibrils 2. Recurrent joint dislocation or subluxation and may improve hypermobility 3. Chronic joint or limb pain 4. Easy bruising Familial Thoracic Aortic Aneurysm 5. Functional bowel disorders (functional gastritis, irritable and Dissection (FAA) bowel syndrome) Some families show an autosomal dominant predisposition 6. Neurally mediated hypotension or postural orthostatic to developing aneurysms in the thoracic aorta whereas others tachycardia develop dilatation anywhere in the aorta. The larger the dilata- 7. High, narrow palate tion, the greater the risk of dissection. In other families, a risk of 8. Dental crowding dissection exists with minimal or no dilatation. Several genetic

174 Volume 14 | Number 1 | January 2012 | Genetics in medicine Marfanoid evaluation | PYERITZ acmg practice guidelines loci have been mapped in families with aortic aneurysm, but aorta and its branches, aortic dilatation and dissection, and most of the genes are yet to be identified. TGFBR2 mutations joint hypermobility.5 Patients have had mutations in one or have been reported in a few families. Two splicing and one mis- another of the receptors for TGFβ. When this condition is sense mutation in the MYH11 gene have been described in two suspected, echocardiography must be augmented by a CT families with FAA and patent ductus arteriosus.15 Occasionally, or magnetic resonance angiogram of the thorax, abdomen, patients with aortic aneurysm will have deformity of the thoracic and pelvis. Because dissection tends to occur at smaller aor- cage (scoliosis, pectus excavatum). These skeletal changes are tic diameters than in MFS, earlier prophylactic aortic root also seen in people with bicuspid aortic valve sequence, which repair is indicated. A variant of LDS strongly resembles the raises the question of whether patients with only ascending aor- vascular form of Ehlers–Danlos syndrome, especially in tic aneurysms are simply failing to express the bicuspid valve. terms of thin skin.

Diagnostic evaluation16 Diagnostic evaluation 1. Physical examination 1. Physical exam 2. Family history 2. Family history 3. Echocardiogram 3. Echocardiogram 4. Dilated eye exam (to exclude MFS) 4. Dilated eye exam (to exclude MFS) 5. Consider gene sequencing 5. Magnetic resonance angiography of the head, neck, 6. Imaging of the vasculature, including the cerebral vascu- thorax, abdomen, and pelvis lature, for those with a genetic mutation that predisposes 6. TGFBR1 and TGFBR2 gene sequencing to diffuse arteriopathy Diagnostic criteria Diagnostic criteria In a patient found to have consistent facial features, bifid uvula, Autosomal dominant family history of dilation or dissection and arterial tortuosity, the diagnosis can be confirmed with of the aortic root, ascending aorta, or descending aorta in the TGFBR testing. Tortuosity can sometimes be isolated (e.g., absence of major criteria for the diagnosis of MFS or another found only in the head and neck), requiring the magnetic reso- connective tissue disorder. nance angiography of the head, neck, thorax, abdomen, and pelvis for a complete evaluation. Management (recommend management by a skilled cardiologist) Management (recommend management by a skilled Aortic dissection is rare in early childhood, but aortic dilation cardiologist) may be present. In most adults, the risk of aortic dissection or Craniosynostosis is treated in the standard manners rupture becomes significant at diameters >5.0 cm. However, Annual echocardiogram if no aortic root dilation mutations in some genes (TGFBR1 and -2) predispose to Echocardiogram at least every 6 months if aortic root dilation dissection at smaller and even normal aortic diameters. Persons is detected with mutations in MYH11, SMAD3, and ACTA2 should be Annual magnetic resonance angiography of the head, neck, considered for repair with a diameter between 4.5–5.0 cm. thorax, abdomen, and pelvis Annual echocardiograms for individuals with small aortic β-blockade. There is no randomized controlled trial of dimensions and slow rate of increase of the dilation in the angiotensin receptor blockade under way. absence of a TGFBR mutation Aortic dilation and dissection in childhood is a feature of Echocardiograms at least every 6 months if the root exceeds LDS, but not for all patients with a mutation in TGFBR1 or 4.5 cm in an adult, the rate of aortic growth exceeds 0.5 cm/ TGFBR2. There is a low threshold for prophylactic aortic year, or significant aortic regurgitation occurs. grafting in LDS. If the progression is rapid, aortic root Imaging of the entire aorta every 2–3 years replacement is recommended at 2.0 cm.17 β-blockade for aortic root dilation. No randomized controlled trial of angiotensin receptor blockade is planned. CCA, BEALS SYNDROME Prophylactic surgical repair if the rate of dilation approaches This condition shows congenital contractures of the elon- 1 cm/year, if there is progression of aortic regurgitation, if the gated digits, elbows, and knees that can improve with physical diameter approaches 5 cm in those with a mutation known therapy. Scoliosis develops during childhood and can become to predispose to earlier dissection, when the diameter is 5.0 severe. The helix of the ear shows overfolding. There is no ecto- cm in those with bicuspid aortic valve, and for a diameter of pia lentis. There is a Marfan-like habitus. Originally, the car- 5.0–5.5 cm for all others. diovascular system was said to be unaffected, but first MVP and more recently aortic dilatation have been described. Every LDS patient thought to have CCA should have echocardiography, The features include characteristic facial features, cran- perhaps on a regular basis, at least during childhood and ado- iosynostosis, bifid uvula or cleft palate, tortuosity of the lescence. Congenital contractures, typically of the digits and

Genetics in medicine | Volume 14 | Number 1 | January 2012 175 acmg practice guidelines PYERITZ | Marfanoid evaluation elbows, also occur in MFS. Some “crumpling” of the ear is also and pelvis. Mutations in a nuclear glucose transporter encoded not uncommon in the general population. Therefore, diagnosis by the SLC2A10 gene have been found.20 of CCA can be difficult. The role of examining the FBN2 locus Monitoring guidelines are the same as those described above for mutations is unclear. for LDS.

Diagnostic evaluation MVP 1. Physical exam In some families, MVP occurs as an autosomal dominant trait, 2. Family history either isolated or in association with an asthenic habitus. Because 3. Echocardiogram the pathogenesis of MVP is varied, the valvular abnormality 4. Dilated eye exam (to exclude MFS) is seen in a number of other hereditary syndromes, including 5. Consider FBN2 gene sequencing dilated cardiomyopathy, myotonic dystrophy, fragile-X syndrome, and some in this Appendix, including MASS, various Diagnostic criteria EDS types, bicuspid aortic valve, and Stickler syndrome. Individuals with CCA typically have a marfanoid habitus; A child with MVP and an asthenic habitus should have aortic flexion contractures of multiple joints including elbows, hips, root measurements taken when MVP monitoring echocardio- knees, and fingers; kyphoscoliosis; muscular hypoplasia; and grams are done. If dilation of the aortic root is found, the child abnormal pinnae (“crumpled” outer helices).18 should be followed as described above for MFS.

Management FAMILIAL ECTOPIA LENTIS Physical therapy for joint manifestations and surgical release Some families show variable skeletal manifestations of MFS of severe contractures along with ectopia lentis. Initially, these cases were said not to Bracing and/or surgical correction of kyphoscoliosis have aortic dilatation, but subsequently some have developed this Echocardiogram every 2 years until adult height reached. If feature and are more appropriately said to have MFS. Mutations no dilation present, repeat if symptomatic or when a major near the 3′-end of FBN1 have been associated with this auto- increase in physical activity is planned. somal dominant condition. If ectopia lentis and 3′ mutation are Annual evaluation by physical exam for scoliosis until adult observed, follow the cardiovascular system as described above height reached for MFS. Aortic root dilation is treated as described above MFS BICUSPID AORTIC VALVE SEQUENCE MASS PHENOTYPE Left-sided flow defects show more familial predisposition than The acronym stands for mitral valve prolapse and myopia, any other general class of congenital heart disease other than an aortic root that may be at the upper limits of normal in conotruncal defects. The causes are unknown, but a defect of caliber, striae atrophicae, and skeletal features reminiscent the neural crest is suspected. The features that show variable of, but less severe than, MFS.19 A few patients designated as expression in families with this sequence are congenital bicus- having MASS have had mutations in FBN1, but most do not. pid aortic valve, dilatation of the ascending aorta (not usually This condition is termed a “phenotype” because there are the sinuses of Valsalva), aortic coarctation, MVP, and thoracic- undoubtedly multiple causes. Importantly, almost all patients cage deformity. Heterozygosity for mutations in NOTCH1 has diagnosed as having MASS over a decade showed no pro- been reported in a few families and in 4% of sporadic cases of gressive aortic root dilatation or aortic dissection (Pyeritz bicuspid aortic valve.21 unpublished). This diagnosis cannot be made with certainty in the absence FAMILIAL TALL STATURE of a multigenerational family history documenting no progres- One family distinguished by pectus excavatum and tall stature sion of aortic root dilation. Therefore, a child who appears to in the proband and tall stature in the relatives had a mutation have the MASS phenotype without a family history should be in FBN1. No one had cardiovascular problems. There has been followed as described above for MFS. no systematic survey of disproportionately tall individuals for other features of MFS or mutations in FBN1. FAMILIAL ARTERIAL TORTUOSITY SYNDROME This condition was first described as a severe condition of FAMILIAL PECTUS EXCAVATUM infancy. Recently, a pleiotropic condition of adults that shows Pectus excavatum occurs as an autosomal dominant trait in autosomal recessive inheritance was described.6 Patients have occasional families. The literature is silent on whether pec- marked tortuosity of the aorta and its branches, and there is a tus carinatum or combined anterior chest defects also occur, predisposition to dissection. They also have telangiectases of the probably because ascertainment has typically been through cheeks, lax skin, high palate, and joint laxity. When this condi- surgeons consulted to repair the excavatum defects. There has tion is suspected, echocardiography must be augmented by a been no systematic survey for other features of MFS or muta- CT or magnetic resonance angiogram of the thorax, abdomen, tions in FBN1.

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FAMILIAL SCOLIOSIS 11. Lacro RV, Dietz HC, Wruck LM, et al. Rationale and design of a randomized 22,23 clinical trial of beta blocker therapy (atenolol) vs. angiotensin II receptor “Idiopathic” scoliosis clearly shows familial predispositions. blocker therapy (losartan) in individuals with Marfan syndrome. Am Heart J There has been no systematic survey for other features of MFS 2007;154:624–631. or mutations in FBN1. 12. Wenstrup RJ, Meyer RA, Lyle JS, et al. Prevalence of aortic root dilation in the Ehlers-Danlos syndrome. Genet Med 2002;4:112–117. 13. Levy HP (updated 14 December 2010). Ehlers–Danlos syndrome, STICKLER SYNDROME hypermobility type. In: GeneReviews at GeneTests: Medical Genetics Occasionally, the person with Stickler syndrome will be consid- Information Resource (database online). Copyright, University of ered initially as having MFS or another connective tissue disor- Washington, Seattle. 1997–2006. http://www.ncbi.nlm.nih.gov/books/ NBK1279/. Accessed 29 November 2011. der. The features that overlap include retrognathia, high-grade 14. Beighton P, Solomon L, Soskolne CL. Articular mobility in an African myopia and retinal detachment, and MVP. population. Ann Rhem Dis 1973;32:413–418. 15. Zhu L, Vranckx R, Van Kien PK, et al. Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and DISCLOSURE patent ductus arteriosus. Nat Genet 2006;38:343–349. The author declares no conflict of interest. 16. Milewicz DM, Regaldo E (updated 11 January 2011). Thoracic aortic aneurysms and aortic dissections. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of references Washington, Seattle. 1997–2006. http://www.ncbi.nlm.nih.gov/books/ 1. DePaepe A, Deitz HC, Devereux RB, Hennekam R, et al. Revised diagnostic NBK1120/. Accessed 29 November 2011. criteria for the Marfan syndrome. Am J Med Genet 1996;62:417–426. 17. Loeys BL, Dietz HC (updated 29 April 2008). Loeys–Dietz syndrome. 2. Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the In: GeneReviews at GeneTests: Medical Genetics Information Resource Marfan syndrome. J Med Genet 2010;47:476–485. (database online). Copyright, University of Washington, Seattle. 3. Beighton P, de Paepe A, Danks D, et al. International nosology of 1997–2006. http://www.ncbi.nlm.nih.gov/books/NBK1130/. Accessed 29 heritable disorders of connective tissue, Berlin, 1986. Am J Med Genet November 2011. 1988;29:581–594. 18. Godfrey M (updated 4 May 2007). Congenital contractural arachnodactyly. 4. Roman MJ, Devereux RB, Kramer-Fox R, et al. Two-dimensional In: GeneReviews at GeneTests: Medical Genetics Information Resource echocardiographic aortic root dimensions in normal children and adults. (database online). Copyright, University of Washington, Seattle. Am J Cardiol 1989;64:507–512. 1997–2006. http://www.ncbi.nlm.nih.gov/books/NBK1386/. Accessed 29 5. Loeys BL, Chen J, Neptune ER, et al. A syndrome of altered cardiovascular, November 2011. craniofacial, neurocognitive and skeletal development caused by mutations 19. Glesby MJ, Pyeritz RE. Association of mitral valve prolapse and systemic in TGFBR1 or TGFBR2. Nat Genet 2005;37:275–281. abnormalities of connective tissue: a phenotypic continuum. JAMA 6. Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by 1989;262:523–528. mutations in TGF-β receptor. N Engl J Med 2006;355:788–798. 20. Coucke PJ, Willaert A, Wessels MW, et al. Mutations in the facilitative 7. Pyeritz RE. Marfan syndrome and related disorders. In: Rimoin DL, Conner glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity JM, Pyeritz RE, Korf BR (eds). Principles and Practice of Medical Genetics, syndrome. Nat Gene 2006;38:452–457. 5th edn. Churchill Livingstone: Philadelphia, 2007; 3579–3624. 21. Mohamed SA, Aherrahrou Z, Liptau H, et al. Novel missense mutations 8. Chow K, Pyeritz RE, Litt HI. Abdominal visceral findings in patients with (p.T596M and p.P1797H) on NOTCH1 in patients with bicuspid aortic Marfan syndrome. Genet Med 2007;9:208–212. valve. Biochem Biophys Res Commun 2006;345:1460–1465. 9. Dietz HC, Loeys B, Carta L, et al. Recent progress towards a molecular 22. Pyeritz RE. Common disorders of connective tissue. In: King RA, Rotter JI, understanding of Marfan syndrome. Am J Med Genet C Semin Med Genet Motulsky AG (eds). The Genetic Basis of Common Diseases, 2nd edn. Oxford 2005;139:4–9. University Press: New York, 2002:638–645. 10. Keane MG, Pyeritz RE. Medical management of Marfan syndrome. 23. Miller NH. Idiopathic scoliosis: cracking the genetic code and what does it Circulation 2008;117:2802–2813. mean? J Pediatr Orthop 2011;31:S49–52.

Genetics in medicine | Volume 14 | Number 1 | January 2012 177 Canadian Journal of Cardiology 30 (2014) 577e589 Position Statement Canadian Cardiovascular Society Position Statement on the Management of Thoracic Aortic Disease Primary Panel: Munir Boodhwani, MD, MMSc (Co-Chair),a Gregor Andelﬁnger, MD, PhD,b Jonathon Leipsic, MD,c Thomas Lindsay, MD, MSc,d M. Sean McMurtry, MD, PhD,e Judith Therrien, MD,f and Samuel C. Siu, MD, SM (Co-Chair)g a Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada b Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada c Department of Radiology, University of British Colombia, Vancouver, British Colombia, Canada d Division of Vascular Surgery, University Health Network, Toronto, Ontario, Canada e Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada f Division of Cardiology, McGill University, Montreal, Quebec, Canada g Division of Cardiology, Western University, London, Ontario, Canada

ABSTRACT RESUM E This Canadian Cardiovascular Society position statement aims to provide Cet enonc edepositiondelaSoci et e canadienne de cardiologie a pour succinct perspectives on key issues in the management of thoracic aortic but de donner des perspectives succinctes sur les aspects cles de la disease (TAD). This document is not a comprehensive overview of TAD and prise en charge de la maladie de l’aorte thoracique (MAT). Ce document important elements of the epidemiology, presentation, diagnosis, and n’est pas un aperçu complet de la MAT, et les el ements importants de management of acute aortic syndromes are deliberately not discussed; l’epid emiologie, du tableau clinique, du diagnostic et de la prise en readers are referred to the 2010 guidelines published by the American charge des syndromes aortiques aigus ne sont delib er ement pas dis- Heart Association, American College of Cardiology, American Association cutes; les lecteurs sont invites à consulter les lignes directrices de 2010 for Thoracic Surgery, and other stakeholders. Rather, this document is a publiees par l’American Heart Association, l’American College of Cardi- practical guide for clinicians managing adult patients with TAD. Topics ology, l’American Association for Thoracic Surgery et les autres parties covered include size thresholds for surgical intervention, emerging thera- prenantes. Ce document est plutôt un guide pratique pour les cliniciens

Thoracic Aortic Aneurysm patients.1,2 Elective intervention on the thoracic aorta carries a much lower risk of mortality and morbidity, and prophylactic Size thresholds for elective thoracic aortic intervention aortic surgery can be life-saving. Thoracic aortic aneurysms are largely asymptomatic until a The decision to perform aortic intervention is a balance sudden and catastrophic event, including aortic rupture or between risks of natural history of the disease vs the risk of the dissection, occurs, and is rapidly fatal in a large proportion of surgical intervention itself, and any additional long-term risks

Received for publication November 8, 2013. Accepted February 1, 2014. experts on this topic with a mandate to formulate disease-speciﬁc recommendations. These recommendations are aimed to provide a reasonable and Corresponding author: Dr Munir Boodhwani, H3405, 40 Ruskin St, practical approach to care for specialists and allied health professionals obliged Ottawa, Ontario K1Y 4W7, Canada. Tel.: þ1-613-761-4313; fax: þ1-613- with the duty of bestowing optimal care to patients and families, and can be 761-5107. subject to change as scientiﬁc knowledge and technology advance and as E-mail: [email protected] practice patterns evolve. The statement is not intended to be a substitute for The disclosure information of the authors and reviewers is available physicians using their individual judgement in managing clinical care in from the CCS on the following websites: www.ccs.ca and/or www. consultation with the patient, with appropriate regard to all the individual ccsguidelineprograms.ca. circumstances of the patient, diagnostic and treatment options available and This statement was developed following a thorough consideration of available resources. Adherence to these recommendations will not necessarily medical literature and the best available evidence and clinical experience. It produce successful outcomes in every case. represents the consensus of a Canadian panel comprised of multidisciplinary

The usefulness of whole-exome sequencing in routine clinical practice

Alejandro Iglesias, MD1, Kwame Anyane-Yeboa, MD1, Julia Wynn, MS2, Ashley Wilson, MS3, Megan Truitt Cho, ScM3, Edwin Guzman, MS3, Rebecca Sisson, MS3, Claire Egan, MS3 and Wendy K. Chung, MD, PhD2,4

Purpose: Reports of the use of whole-exome sequencing in clini- of additional planned testing in all patients, screening for additional cal practice are limited. We report our experience with whole-exome manifestations in eight, altered management in fourteen, novel ther- sequencing in 115 patients in a single center and evaluate its feasibil- apy in two, identification of other familial mutation carriers in five, ity and clinical usefulness in clinical care. and reproductive planning in six. Methods: Whole-exome sequencing was utilized based on the judg- Conclusion: Our results show that whole-exome sequencing is fea- ment of three clinical geneticists. We describe age, gender, ethnic- sible, has clinical usefulness, and allows timely medical interventions, ity, consanguinity, indication for testing, family history, insurance, informed reproductive choices, and avoidance of additional testing. laboratory results, clinician interpretation of results, and impact on Our results also suggest phenotype expansion and identification of patient care. new candidate disease genes that would have been impossible to Results: Most patients were children (78.9%). The most common diagnose by other targeted testing methods. indications for testing were birth defects (24.3%) and developmen- Genet Med advance online publication 5 June 2014 tal delay (25.2%). We identified four new candidate human disease genes and possibly expanded the disease phenotypes associated with Key Words: clinical evaluation; genetic testing; undiagnosed genetic five different genes. Establishing a diagnosis led to discontinuation disorders; whole-exome sequencing

introduction WES as part of routine clinical care in our clinical genetic The use of whole-exome sequencing (WES) in the clinical practice at a single institution. Our patients were tested before setting has increased significantly in the past 2 years since the American College of Medical Genetics and Genomics rec- clinical laboratories started offering it. Many patients with ommendations on incidental findings were implemented by rare disorders now have diagnoses made through WES and the laboratories3; therefore, our study focuses only on the pri- Genet Med had previously spent years on an uninformative diagnostic mary findings. Our experience should assist other clinicians odyssey enduring costly, time consuming, and sometimes in implementing WES into their clinical practice because we invasive procedures associated with medical risks that are have addressed practical concerns including patient education 2014 stressful for families and providers and imposing a heavy in pretest counseling, consent, insurance coverage, turnaround burden on the health-care system. In the postmortem set- time, yield of testing, updates of test results, and impact on 00 ting, WES offers the opportunity to obtain maximal genetic clinical care. We have found that WES significantly improves information when DNA can be limiting. Often WES is a less our diagnostic ability; we have addressed many of the practical 00 expensive option than serial genetic testing for conditions problems of its clinical implementation and routinely use WES characterized by genetic heterogeneity due to involvement as a primary test in patients’ genetic evaluation. 27December2013 of a large number of genes. For families concerned about the risk of recurrence or considering having additional children, MATERIALS AND METHODS 23April2014 time is often precious and female fertility can be limited. For We retrospectively reviewed the charts of 115 patients who all these reasons, a comprehensive method of genomic test- were clinically evaluated by one of three board-certified clini- 10.1038/gim.2014.58 ing such as WES is appealing, but data about its use in the cal geneticists (W.K.C., K.A.-Y., and A.I.) and one of six board- clinical setting are limited. certified genetic counselors (J.W., A.W., E.G., M.T.C., R.S., and The available evidence of the use of WES in a clinical setting C.E.) at Columbia University Medical Center from October Genetics in Medicine has largely been an extension of a previous research protocol1 2011 to July 2013 and for whom WES had been completed or a comparison of traditional diagnostic methods and WES.2 in that time period. The study was approved by the Columbia 00 Here we report a series of our first 115 patients evaluated by University institutional review board.

00 1Division of Clinical Genetics, Department of Pediatrics, Columbia University Medical Center, New York, New York, USA; 2Division of Molecular Genetics, Department of Pediatrics, Columbia University Medical Center, New York, New York, USA; 3Division of Clinical Genetics, Department of Pediatrics, New York Presbyterian Hospital, New York, New York, USA; 4Department of Medicine, Columbia University Medical Center, New York, New York, USA. Correspondence: Alejandro Iglesias ([email protected]) Submitted 27 December 2013; accepted 23 April 2014; advance online publication 5 June 2014. doi:10.1038/gim.2014.58

5June2014 Genetics in medicine 1 HOW TO UNDERSTAND IT Exome sequencing: how to understand it

M J Keogh,1,2 D Daud,3 P F Chinnery2

1James Cook University Hospital, INTRODUCTION scope of this review, but there is a com- Middlesbrough, UK ‘ ’ 2 The terms next generation sequencing , prehensive list at the UK Genetic Testing Wellcome Centre for ‘ ’ ‘ Mitochondrial Research, Institute second generation sequencing , exome Network website (UKGTN, http://www. of Genetic Medicine, sequencing’, and ‘whole genome sequen- ukgtn.nhs.uk/gtn/Home). Tests not avail- International Centre for Life, cing’ are gradually migrating from the able through the UKGTN can be accessed Newcastle University, Newcastle echelons of esoteric molecular genetics through European or even North upon Tyne, UK 3Newcastle University, journals into mainstream neurological American providers (eg, http://eddnal. Newcastle, UK practice. These techniques, in their com/), but these often incur substantial technological infancy only 5 years ago, cost. Other testing is carried out through Correspondence to Prof P F Chinnery, Wellcome have become widely adopted into clinical research laboratories with a special inter- Centre for Mitochondrial research over the past 2–3 years, greatly est in the disease, but these are not Research, Institute of Genetic advancing our understanding of subject to the same quality control as a Medicine, International Mendelian disorders. We are beginning certified laboratory, and their results must Centre for Life, Newcastle University, Newcastle Upon to see their first applications to sporadic be interpreted with caution. Tyne NE1 3BZ, UK; neurological disease; exponential growth If these tests come back negative—and [email protected] in this area is inevitable. This article aims assuming a genetic cause remains most to enable the neurologist to understand likely—then there are three possibilities: Published Online First 1 June 2013 what whole exome sequencing is, how it 1. The correct gene was not tested.Thiscould works, when and how it is useful in neur- be because the patient has an atypical ology, and the potential benefits and lim- phenotype, so the relevant test was not con- itations of the techniques. sidered or performed. 2. The correct gene was tested, but the mutation was not ‘picked up’. This could be IN PRACTICE because the diagnostic test is not compre- Over the past two decades, advances in hensive—for example, deletions may not molecular genetic diagnostics have dra- be routinely tested for, or the mutation matically expanded the field of neuroge- could be a regulatory variant upstream of netics, which now includes many the coding region, and thus not picked up ostensibly sporadic diseases presenting in using standard sequencing protocols. routine neurological practice. Although 3. The disease gene is not known. neurogenetic disorders vary widely clinic- In any of these scenarios, it is like ally, the overall approach to diagnosis is trying to find a needle in a haystack—or, consistent. to be precise, a mutation in a genome of The clinician should first fully exclude three billion nucleotide base pairs. Until non-genetic causes. This involves careful recently, the approach to this problem phenotyping using the tried and tested was limited. neurological approach: history, examination, and well-considered clinical tests. This may identify sporadic diseases that Next generation sequencing might be amenable to treatment—for Many of the molecular diagnostic assays in example, vasculitis in suspected axonal clinical practice involve ‘first generation’ or Charcot–Marie–Tooth disease, or vitamin ‘Sanger sequencing’.Thisisused,for E deficiency in juvenile ataxia. example, to test for a NOTCH3 mutation The next step—at least in the UK’s in CADASIL (cerebral autosomal dominant National Health Service—involves tar- arteriopathy with subcortical infarctions geted mutation screening focused on spe- and leukoencephalopathy). Sanger sequen- To cite: Keogh MJ, Daud D, cific genetic causes of a particular cing can read a DNA sequence of up to Chinnery PF. Pract Neurol phenotype. A detailed discussion of the around 1000 bases. However, this can only 2013;13:399–407. different tests on offer is beyond the be within the predefined region or gene of

Keogh MJ, et al. Pract Neurol 2013;13:399–407. doi:10.1136/practneurol-2012-000498 399 ACMG Practice Guidelines

American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss

Raye L. Alford, PhD, FACMG1, Kathleen S. Arnos, PhD, FACMG2, Michelle Fox, MS, CGC3,4, Jerry W. Lin, MD, PhD1, Christina G. Palmer, PhD, FACMG5,6, Arti Pandya, MD, FACMG7, Heidi L. Rehm, PhD, FACMG8, Nathaniel H. Robin, MD, FACMG9, Daryl A. Scott, MD, PhD10,11 and Christine Yoshinaga-Itano, PhD12; ACMG Working Group on Update of Genetics Evaluation Guidelines for the Etiologic Diagnosis of Congenital Hearing Loss; for the Professional Practice and Guidelines Committee

Disclaimer: This guideline is designed primarily as an educational resource for clinicians to help them provide quality medical services. Adherence to this guideline is completely voluntary and does not necessarily assure a successful medical outcome. This guideline should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this guideline. Clinicians also are advised to take notice of the date this guideline was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.

Hearing loss is a common and complex condition that can occur and the effectiveness of clinical care. These concerns can be mini- at any age, can be inherited or acquired, and is associated with a mized when genetic and other health-care services are provided in remarkably wide array of etiologies. The diverse causes of hearing a linguistically and culturally sensitive manner. This guideline offers loss, combined with the highly variable and often overlapping pre- information about the frequency, causes, and presentations of hear- sentations of different forms of hearing loss, challenge the ability ing loss and suggests approaches to the clinical evaluation of deaf of traditional clinical evaluations to arrive at an etiologic diagnosis and hard-of-hearing individuals aimed at identifying an etiologic for many deaf and hard-of-hearing individuals. However, identify- diagnosis and providing informative and effective patient education ing the etiology of a hearing loss may affect clinical management, and genetic counseling. Genet Med improve prognostic accuracy, and refine genetic counseling and assessment of the likelihood of recurrence for relatives of deaf and Genet Med advance online publication 20 March 2014 hard-of-hearing individuals. Linguistic and cultural identities asso- Key Words: genetics evaluation; deaf; Deaf; genetic counseling; 2014 ciated with being deaf or hard of hearing can complicate access to genetic testing; guideline; hard of hearing; hearing loss

00 DEFINITIONS 00 Deaf: a community with a distinct culture and language hard of hearing: an auditory phenotype characterized by a par- shaped by the experience of being deaf or hard of hear- tial loss of the ability to hear 6January2014 ing, which may include deaf, hard-of-hearing, and hearing hearing loss: an auditory phenotype characterized by any individuals degree of loss of the ability to hear; depending on cause, hearing 6January2014 deaf: an auditory phenotype characterized by a total or near- loss can be temporary or permanent—this guideline focuses on total loss of the ability to hear permanent hearing loss 10.1038/gim.2014.2

Genetics in Medicine 1Bobby R. Alford Department of Otolaryngology–Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, USA; 2Department of Science, Technology, and Mathematics, Gallaudet University, Washington, DC, USA; 3Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA; 4Department of Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA; 5Department of Psychiatry 16 and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA; 6Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA; 7Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, USA; 8Laboratory for Molecular Medicine, Harvard Medical School, Cambridge, Massachusetts, USA; 9Department of Genetics, University 4 of Alabama at Birmingham, Birmingham, Alabama, USA; 10Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; 11Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, USA; 12School of Medicine, University of Colorado Denver, Aurora, Colorado, USA. Correspondence: Raye L. Alford ([email protected])

Submitted 6 January 2014; accepted 6 January 2014; advance online publication 20 March 2014. doi:10.1038/gim.2014.2

20March2014 Genetics in medicine | Volume 16 | Number 4 | April 2014 347 ACMG Practice Guidelines ALFORD et al | ACMG guideline: hearing loss

INTRODUCTION • The laterality and symmetry of the hearing loss—unilat- Two to three of every 1,000 children born in the United States eral or bilateral, symmetric or asymmetric; are deaf or have a hearing loss significant enough to affect speech • The stability of the hearing loss—progressive, nonpro- and language development.1 Early intervention has been shown gressive, or fluctuating; to be effective in facilitating speech and language development in • The degree of hearing loss—slight (16–25 decibels (dB)), deaf and hard-of-hearing children.2 As a result, newborn hear- mild (26–40 dB), moderate (41–55 dB), moderately ing screening, which began in 2001, is now mandated through- severe (56–70 dB), severe (71–90 dB), or profound (91 dB out the United States. Not all childhood hearing loss is present at or greater)18; and birth, however, and hearing screening is recommended through- • The configuration of the hearing loss as seen on audio- out childhood and adolescence to identify children with later- metric analysis—sloping, flat, rising, or midfrequency onset hearing loss and to permit early intervention.3,4 (cookie-bite) loss. Ninety-five percent of newborns with hearing loss identified by newborn hearing screening programs are born to hearing Hearing loss may also be described according to an apparent parents, obscuring the fact that the majority of newborns have pattern of inheritance—autosomal recessive, autosomal domi- a hereditary cause for their hearing loss.5,6 Analysis of family nant, X-linked, or matrilineal (mitochondrial). If a specific eti- history data from school-aged children in the United States ology is known, descriptions of hearing loss may also include estimated that up to 60% of educationally significant congeni- the etiologic diagnosis, such as Usher syndrome type 1–related tal and early-onset hearing loss is caused by genetic factors.5,6 hearing loss or GJB2-related hearing loss.15,16,19,20 The majority of genetic hearing loss is inherited in an autosomal recessive pattern and often presents in the absence of a GENETIC AND NONGENETIC ETIOLOGIES OF positive family history for hearing loss. One gene, GJB2, which HEARING LOSS encodes the gap junction protein connexin 26, accounts for Hearing loss is among the most etiologically heterogeneous the largest proportion of autosomal recessive early childhood disorders, with more than 400 genetic syndromes that include hearing loss in many populations.7 hearing loss as a feature, more than 100 genes associated with The prevalence of hearing loss increases with age, with 40– nonsyndromic genetic hearing loss, and a number of nonge- 50% of the population experiencing hearing loss by age 75.8 The netic causes.20,21 Genes associated with syndromic and non- contribution of genetic causes to cases of adult-onset hearing syndromic genetic hearing loss encode a variety of proteins loss is less clear. However, it is evident that a significant propor- involved in the development and function of the auditory sys- tion of adult-onset hearing loss is likely to be caused, or strongly tem, including transcription factors, structural proteins, gap influenced, by genetic factors.9–14 junction proteins, and ion channels, to name just a few. The goal of a genetics evaluation for deaf and hard-of-hear- An estimated 30% of genetic hearing loss is syndromic. A ing individuals of any age is to identify an etiologic diagnosis few syndromes, such as Pendred (enlarged vestibular aqueduct, and, in doing so, enable implementation of an individualized thyroid problems), Usher (retinitis pigmentosa), Waardenburg health-maintenance strategy.15–17 Identification of a previously (pigmentary anomalies), and branchio-oto-renal (branchial unrecognized syndromic form of hearing loss can be particu- arch and renal anomalies) syndromes, account for substan- larly important because it may allow early management of asso- tial percentages of hearing loss in some populations.20,22–25 ciated medical concerns. Obtaining an etiologic diagnosis also Syndromic hearing loss may be transmitted as an autosomal provides the basis for precise genetic counseling that includes recessive, autosomal dominant, X-linked, or matrilineal trait. an accurate estimation of the chances for recurrence of hearing A review of individual conditions can be found in Hereditary loss within families. Hearing Loss and Its Syndromes by Toriello and Smith20 and the online database GeneReviews.19 AUDIOMETRIC AND CLINICAL ASPECTS OF For some syndromic forms of hearing loss, such as Usher HEARING LOSS syndrome or Pendred syndrome, the nonauditory features can Hearing loss is typically described in terms related to its clini- be subtle, especially in early childhood. For others, hearing loss cal presentation. In general, hearing loss is categorized as either is not the presenting finding or the most pressing concern. For syndromic or nonsyndromic, depending on the presence or many syndromic forms of hearing loss, there is marked vari- absence of associated defects in other organ systems. Hearing ability in the phenotypic presentation and in the age of onset loss is also typically described by the following: of syndromic features. This variability can exist both between and within families. For example, hearing loss is observed in • The age of onset—congenital, prelingual (before the only 20–50% of individuals with Waardenburg syndrome. As acquisition of speech), postlingual (after the acquisition a result, this diagnosis can be easily missed if specific infor- of speech), adult-onset, or presbycusis (age-related late- mation about pigmentary changes or gastrointestinal distur- onset hearing loss); bances is not elicited.26 Furthermore, some hereditary forms of • The type of hearing loss—sensorineural, conductive, hearing loss, such as neurofibromatosis type 2, enlarged vestib- mixed, or auditory neuropathy; ular aqueduct syndrome, and Pendred syndrome, may present

348 Volume 16 | Number 4 | April 2014 | Genetics in medicine ACMG guideline: hearing loss | ALFORD et al ACMG Practice Guidelines initially as unilateral hearing loss.19,20,27–29 Given the challenges in 40–50% of individuals aged 75 and older. Presbycusis gen- that can exist in distinguishing between syndromic and non- erally affects higher frequencies of sound disproportionately, syndromic forms of hearing loss, all children and adolescents making it difficult for those with presbycusis to under- showing hearing loss without a known etiology, e.g., confirmed stand speech.8 Men have presbycusis more frequently than GJB2 mutations or documented congenital cytomegalovirus women.56 Presbycusis is a complex condition influenced by (CMV) infection, should be evaluated for syndromic condi- genetic and environmental factors.13 Much of the literature tions by a clinical geneticist.15,16 about age-related hearing loss has focused on environmen- An estimated 70% of genetic hearing loss is nonsyndromic. tal factors such as noise exposure.9,57,58 More recently, how- Nonsyndromic hearing loss may be transmitted as an auto- ever, several susceptibility loci for age-related hearing loss somal recessive (~80%), autosomal dominant (~15%), or have been identified. Genes implicated in this process using X-linked trait (~1%).20 In addition, matrilineal (mitochon- linkage and genome-wide association studies include genes drial) transmission of nonsyndromic hearing loss occurs with previously implicated in other forms of hearing loss (such as a frequency of ~1% in Western nations but has a slightly higher KCNQ4 and ACTG1), and genes involved in oxidative stress incidence in Spain and East Asian countries including China, (such as GRM7, GRHL2, mitochondrial oxidative genes, and Mongolia, Korea, and Japan.30,31 N-acetyltransferase).9,10,12–14, 20 Of particular note, the DFNB1 locus, which includes the Certain environmental (nongenetic) factors play a major GJB2 gene encoding the gap junction protein connexin 26 and etiologic role in hearing loss.59 In the United States, congenital the GJB6 gene encoding the gap junction protein connexin 30, CMV infection is the most common nongenetic cause of hear- accounts for an estimated 50% of all autosomal recessive non- ing loss among children. of the 20,000-40,000 infants born with syndromic hearing loss and 15–40% of all deaf individuals in congenital CMV infection each year, 90% have no detectable a variety of populations.7,32–38 More than 150 deafness-causing clinical abnormalities at birth, yet 10–15% of these asymptom- variants have been identified in GJB2, but a few common muta- atic infants will develop sensorineural hearing loss which can tions account for a large percentage of alleles in several popu- present in early childhood, can be unilateral or bilateral, and lations.7,34–36 GJB2-related hearing loss is sensorineural, usually is often progressive.60–62 As a result, congenital CMV infection present at birth, typically bilateral and nonprogressive, and can may go undetected even in children who undergo newborn range from mild to profound in severity. However, progressive hearing screening and receive a thorough physical examination or later-onset hearing loss—with infants passing their new- in the neonatal period.16,20,62 born hearing screen—have also been described, particularly in Congenital rubella, which was a common cause of hearing association with nontruncating mutations.39–42 Nonsyndromic loss in the mid-1960s, occurs less frequently in Western popula- hearing loss due to mutations at the DFNB1 locus may also tions today as a result of successful immunization programs.63,64 be caused by (i) interaction of a GJB2 mutation on one allele According to the World Health Organization, no cases of and a deletion involving GJB6 on the other allele or (ii) bial- endemic rubella infection are known to have occurred in the lelic deletions involving GJB6.43–45 GJB6 deletions have been Americas between 2009 and 2012.65 Similarly, the occurrence observed in multiple populations, although they appear to be a of postmeningitic hearing loss in children has been substan- relatively uncommon explanation for hearing loss in the United tially reduced in developed countries as a result of vaccination States.46–48 Notably, hearing loss caused by certain dominant against Haemophilus influenzae.66 However, other environmen- mutations in GJB2, although uncommon, may present as a syn- tal causes for hearing loss—including prematurity and expo- dromic hearing loss, with associated skin findings.49–51 sure to noise or ototoxic drugs such as aminoglycosides and Nonsyndromic mitochondrial hearing loss is character- cyclophosphamides (which may have a genetically determined ized by audiograms that fall into the moderate-to-profound predisposition in some cases)—persist in the United States range and is associated with variants in either the MT-RNR1 today.20, 67–69 gene encoding the mitochondrial 12S ribosomal RNA or the MT-TS1 gene encoding the mitochondrial transfer RNA THE IMPORTANCE OF GENETIC EVALUATION Ser(UCN).30,31,52 Of particular note, mutations in MT-RNR1 are AND GENETIC COUNSELING FOR DEAF AND associated with predisposition to aminoglycoside ototoxicity.53 HARD-OF-HEARING INDIVIDUALS Hearing loss in individuals exposed to aminoglycoside When a genetic etiology is possible, a clinical genetics evalua- antibiotics who carry susceptibility mutations in MT-RNR1 is tion, including genetic counseling, offers a number of poten- bilateral, severe to profound, and typically develops within a tial benefits for children and adults with hearing loss and their few days to weeks after administration of any amount, including families. Benefits can include providing etiologic information, just a single dose, of an aminoglycoside antibiotic.54 Studies offer identifying (or allaying concerns about) comorbidities that may conflicting findings with regard to the likelihood of hearing need referral for specialty care, planning for future medical and loss in individuals carrying a deafness-causing variant in educational needs, facilitating estimations of the likelihood of MT-RNR1 who are not exposed to aminoglycosides.53–55 recurrence, allowing families to better plan for the birth of a Age-related hearing loss, or presbycusis, is a common neu- deaf or hard-of-hearing child, relieving the guilt that some par- rosensory deficit. In the United States, presbycusis is present ents may feel about having a child with hearing loss, enhancing

Genetics in medicine | Volume 16 | Number 4 | April 2014 349 ACMG Practice Guidelines ALFORD et al | ACMG guideline: hearing loss psychological well-being, dispelling misinformation, and with features of Waardenburg syndrome type II, or sequenc- facilitating referral for unrelated hereditary conditions such ing of MYO7A or USH2A, the most common genes involved in as familial cancer.48,70–79 Furthermore, if mitochondrial DNA Usher syndrome types I and II, respectively.90,91 Such screening mutations associated with genetic susceptibility to aminoglyco- can also be cost effective in individuals with genetically hetero- side ototoxicity are discovered, it may be possible for relatives to geneous hearing loss phenotypes when a single gene is respon- avoid precipitating medications.53–55 sible for a significant percentage of cases. For example, GJB2 As with any genetics evaluation, clear communication between gene sequencing can identify the underlying etiology for many the genetics professionals and their patients is important for the individuals whose clinical presentation is consistent with auto- provision of effective genetics services. Deaf and hard-of-hearing somal recessive nonsyndromic hearing loss. individuals use a variety of communication methods, includ- Today, tests based on next-generation sequencing (NGS) ing spoken and signed language, lip reading, and written notes. technologies are rapidly replacing many single gene–sequencing Special training may be needed to optimize communication tests for hearing loss (Figure 1). These tests use disease-targeted between individuals with hearing loss and genetics professionals. exon capture, whole-exome sequencing (WES), or whole- Such training may include (i) training sign language interpret- genome sequencing (WGS) strategies. The main advantage of ers in medical and genetics terminology and (ii) training genetics these tests is their ability to address the problem of genetic het- professionals to work effectively with sign language interpreters erogeneity, wherein many different genes result in phenotypes and use a variety of communication aids, including videophones, that cannot be easily distinguished clinically.92–96 Several NGS video relay services, instant messaging, and visual aids.80 tests are now clinically available and can be found by querying In addition, deafness is considered by some to be a nonmedi- the GeneTests and Genetic Testing Registry websites.97,98 cal trait. Many deaf individuals consider themselves to be part NGS tests that use disease-targeted exon-capture approaches of a linguistic and cultural minority group, viewing their deaf- restrict sequencing to specific genes, such as genes known to be ness as a neutral or positive trait.81,82 By contrast, the medical associated with hearing loss. Such tests can provide excellent perspective—which views deafness as a pathology—is perva- coverage of the genes selected for study but are limited by our sive among most hearing individuals and some deaf individu- present knowledge of which genes are involved in hearing loss. als. This difference in perspective may affect the willingness of Furthermore, some tests may sequence only a subset of the genes some individuals to obtain genetic services and genetic coun- known to be associated with hearing loss. WES is also based on seling.83,84 However, when given accurate information about exon capture but does not rely on a list of genes involved in a par- the nature of genetic counseling and how to obtain a referral, ticular disease process. Instead, WES seeks to evaluate all exons Deaf adults are often interested in receiving genetic services in in the genome for variations. This approach can identify variants order to learn more about themselves and why they are deaf or in known hearing loss–related genes and genes that have yet to hard of hearing. In addition, many Deaf and hard-of-hearing be associated with hearing loss. WGS is not limited to screening individuals report an enhanced sense of self-understanding and exons and therefore has the potential to identify changes outside self-identity, as well as an enhanced cultural and group identity, of exons that may be related to hearing loss. as a result of genetic testing.72,85 Providing genetic services in a The ability of WES and WGS approaches to detect a larger linguistically and culturally sensitive manner has been shown subset of all hearing loss–related changes needs to be balanced to improve outcomes such as genetics knowledge and under- with the difficulties in interpretation that come from identi- standing.86,87 Furthermore, using neutral or balanced termi- fying an ever-increasing number of variants, the challenge of nology, such as “chance” instead of “risk,” “deaf” or “hearing” causally linking variants in new genes to hearing loss, and the instead of “affected” or “unaffected,” and exercising caution likelihood of identifying genetic susceptibilities unrelated to in the use of terms such as “handicapped,” “pathology,” and hearing loss (i.e., incidental findings).99 In 2013, the ACMG “impairment” can enhance the provision of genetic services to published recommendations for reporting incidental findings deaf and hard-of-hearing individuals and their families.86,88,89 from genomic sequencing.100 Furthermore, not all regions of the genome are efficiently GENETIC TESTING FOR THE ETIOLOGIC captured and analyzed by current exon-capture or WGS DIAGNOSIS OF HEREDITARY HEARING LOSS approaches, and large deletions and duplications, in addition Historically, molecular diagnostic tests for hearing loss have to copy-number and structural variations, may not be effi- used genotyping or DNA sequencing to identify specific hear- ciently detected.99 These limitations of NGS technologies may ing loss variants or to screen individual genes, or small collec- necessitate use of alternative or complementary genetic testing tions of genes, for changes associated with hearing loss. This strategies in some cases. approach has proven to be effective in cases in which there is a NGS technologies are expected to continue to improve over single gene, or limited number of genes, responsible for a subtype time, but it will always be important to pay close attention to the of hearing loss. Examples include SLC26A4 gene sequencing in performance characteristics of tests, including coverage, ana- individuals suspected of having Pendred syndrome, PAX3 gene lytic sensitivity, the genes that are and are not analyzed, and the sequencing in individuals with features of Waardenburg syn- types of mutations that are and are not detected. In some cases, drome type I, MITF and SOX10 gene sequencing in individuals it may be helpful to have tests performed in laboratories that

350 Volume 16 | Number 4 | April 2014 | Genetics in medicine ACMG guideline: hearing loss | ALFORD et al ACMG Practice Guidelines

Medical and birth history Audiometric assessment of hearing loss Three-generation pedigree and family medical history Physical examination

Suspect acquired hearing loss?

Ye s No

Provide CMV testing, imaging, or Provide pre-test genetic counseling and genetic testing as clinically indicated: other testing based on suspected If syndromic hearing loss is suspected, consider targeted gene testing based on etiology (e.g., rubella, meningitis) suspected diagnosis; If nonsyndromic hearing loss is suspected, consider single-gene tests such as GJB2 and GJB6, gene panel tests, or NGS testing based on history and findings Provide imaging or other testing as appropriate for suspected diagnosis Acquired etiology confirmed?

Ye s No or inconclusive Genetic etiology confirmed?

Reconsider potential acquired and genetic etiologies Ye s No or inconclusive Provide additional testing and imaging based on findings

Provide treatment as clinically indicated Provide follow-up counseling, including genetic counseling, as needed, based on genetic and other test results and findings Provide referrals to specialists, as needed, based on genetic and other test results and findings Provide follow-up care at periodic intervals based on genetic and other test results and findings, and patient needs

Figure 1 Graphic overview of approaches to the clinical evaluation and etiologic diagnosis of hearing loss. CMV, cytomegalovirus; NGS, next- generation sequencing. focus on genetic causes of hearing loss because these laborato- hearing loss is due to CMV infection, especially if obtained in ries may be more likely to report test performance with respect older children who may have been exposed to CMV after birth. to hearing-related genes and to have developed approaches to Recent algorithms for the evaluation of hearing loss suggest specifically analyze relevant regions of the genome that may be that other nongenetic tests, such as computed tomography, refractory to more general NGS approaches.92–96,99 magnetic resonance imaging, renal ultrasonography, elec- trocardiography, and ophthalmologic consultation, have an OTHER TESTING IMPORTANT TO THE ETIOLOGIC important role because their results can guide genetic testing DIAGNOSIS OF HEARING LOSS or interpretation of DNA sequence variants.106 For example, Because CMV remains a common cause of pediatric hearing temporal bone imaging is commonly recommended to look for loss, testing for congenital CMV infection by rapid culture or an enlarged vestibular aqueduct, which would prompt genetic polymerase chain reaction of saliva or urine samples from new- testing for Pendred syndrome.27,107,108 However, many nonge- borns is recommended as an initial test once a newborn hearing netic tests have low diagnostic yield in patients with hearing loss is confirmed (Figure 1). However, testing for CMV is most loss.109 Furthermore, recent advances in genetic testing tech- diagnostic when done before ~6 weeks of age.101–105 A negative nologies that permit the analysis of many genes simultaneously result most likely excludes CMV as the cause of the hearing at rapidly decreasing cost may soon prompt reassessment of the loss, but a positive result may not necessarily indicate that the clinical utility of certain nongenetic tests as part of the initial

Genetics in medicine | Volume 16 | Number 4 | April 2014 351 ACMG Practice Guidelines ALFORD et al | ACMG guideline: hearing loss workup for the etiologic diagnosis of hearing loss. Such reas- • The pedigree and family medical history should focus sessments will need to consider the clinical utility of various on identifying the following: nongenetic tests versus the risks associated with those tests, such – First- and second-degree relatives with hearing loss as the clinical utility of computed tomography and magnetic or with features commonly associated with hearing resonance imaging versus the risks associated with radiation loss (such as pigmentary, branchial, or renal anom- exposure and sedation.17,109 As evidence for the clinical utility alies) or sudden cardiac death; of NGS tests for the etiologic diagnosis of hearing loss is accu- – A pattern of inheritance; mulated and evaluated, physicians should continue to rely on – Ethnicity and country of origin; their best clinical judgment and consider the use of nongenetic – A common origin from ethnically or geographically tests for the evaluation of hearing loss on a case-by-case basis. isolated areas; and For example, unless cochlear implantation is being consid- – Consanguinity. ered, auditory neuropathy is detected, progressive hearing loss • The physical examination should focus on dysmor- is identified, or other specific clinical concerns exist, it could phic and other physical findings such as the following: be argued that temporal bone imaging might, in some cases, – Unusual facial appearance, with attention to be better used as a complement or follow-up to genetic testing asymmetry; rather than as a part of the initial diagnostic evaluation.109,110 In – Pigmentary anomalies; addition, in the absence of specific clinical concerns or family – Neck, skin, facial, or ear anomalies; history, tests such as electrocardiographic studies, thyroid func- – Neurological abnormalities; tion testing, urinalysis, and renal ultrasonography might also – Balance disturbances; be postponed until results of genetic testing are obtained, and – Skeletal abnormalities; and then ordered as clinically indicated.109,111,112 – Other unusual physical findings. 2. For individuals with findings that suggest a syndromic GUIDELINE genetic etiology for their hearing loss, 1. All newborns and infants with confirmed hearing loss • Pretest genetic counseling should be provided, and, should undergo a comprehensive evaluation in which with patient’s informed consent, genetic testing, if patient-focused medical and birth histories and a three- available, should be ordered to confirm the diagno- generation pedigree and family medical history are sis—this testing may include single-gene tests, hear- obtained, and a physical examination that focuses on ing loss sequencing panels, WES, WGS, chromosome dysmorphic physical findings is performed. Evaluation analysis, or microarray-based copy-number analysis, of children and young adults with hearing loss should depending on clinical findings; follow a similar approach. Evaluation of deaf or hard- • Appropriate studies should be undertaken to deter- of-hearing adults should be customized based on the mine whether other organs are involved; and age of onset and other characteristics of the hearing loss • Appropriate near-term and long-term screening and (Figure 1). management should be arranged, including referrals • The medical and birth histories may be helpful in dif- to specialists, as indicated by the associated manifes- ferentiating between acquired versus inherited causes tations of the particular syndrome. of hearing loss. Elements of medical and birth histo- 3. For individuals lacking physical findings suggestive of a ries focused on hearing loss include the following: known syndrome and having medical and birth histories – Prenatal history, including maternal infections that do not suggest an environmental cause of hearing (e.g., CMV, rubella) and illnesses (e.g., syphilis), or loss, a tiered diagnostic approach should be implemented. medication or drug exposures (e.g., thalidomide, • Pretest genetic counseling should be provided, and, retinoic acid)113,114; with patient’s informed consent, genetic testing – Neonatal history, including premature birth, low should be ordered. birth weight, birth hypoxia, hyperbilirubinemia, – Single-gene testing may be warranted in cases in sepsis, and exposure to ototoxic medications; which the medical or family history, or presentation – Postnatal history, including viral illnesses, bacterial of the hearing loss, suggests a specific etiology. For meningitis, head trauma, noise exposure, and expo- example, testing for mitochondrial DNA mutations sure to ototoxic medications; and associated with aminoglycoside ototoxicity may be – Audiometric assessment of the hearing loss, includ- considered for individuals with a history of use of ing sensorineural versus conductive or mixed hear- aminoglycoside antibiotics. ing loss; age of onset; progressive, nonprogressive, – In the absence of any specific clinical indications and or fluctuating nature of the hearing loss; laterality, for singleton cases and cases with apparent auto- symmetry, severity, and configuration of the hear- somal recessive inheritance, the next step should ing loss; and the presence or absence of vestibular be testing for DFNB1-related hearing loss (due to dysfunction or auditory neuropathy. mutations in GJB2 and adjacent deletions in GJB6).

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– If initial genetic testing is negative, genetic testing and support of deaf and hard-of-hearing individuals using gene panel tests, NGS technologies such as and their families as their needs change over time. large sequencing panels targeted toward hearing • For cases in which the genetic evaluation failed to loss–related genes, WES, or WGS may be consid- identify an underlying cause, periodic follow-up care ered. Because several tests are clinically available, every 3 years with a geneticist may be appropriate for the clinician must be aware of the genes included in several reasons. First, subtle features of syndromic the test (panel) chosen and the performance charac- forms of hearing loss may not be apparent at birth or teristics of the platform chosen, including coverage, early in childhood but may appear as deaf or hard-of- analytic sensitivity, and what types of mutations will hearing individuals grow into adulthood. These may be detected. It should be noted that the cost of these prompt additional medical tests or referrals for spe- new genetic sequencing technologies is decreasing cialty care. Second, follow-up visits offer the opportu- so rapidly that a tiered approach to testing may soon nity to inform individuals about new genetic tests that no longer be cost effective. In particular, for large may have become available or changes in the interpre- sequencing panels targeted toward hearing loss– tation of previous test results as medical knowledge related genes, it may, in some cases, already be more advances. Finally, follow-up visits may also help iden- cost effective to use NGS technologies as the initial tify clinical concerns unrelated to hearing loss, for test in the evaluation of hearing loss. However, issues which referral for specialty care may be appropriate related to genomic testing, such as the likelihood of (Figure 1). incidental findings, will have to be addressed. 5. Regardless of whether genetic test results are positive, – If genetic testing reveals mutation(s) in a hearing negative, or inconclusive, results should be communi- loss–related gene, mutation-specific genetic coun- cated through the process of genetic counseling. seling should be provided, followed by appropriate medical evaluations and referrals. DISCLOSURE – If genetic testing fails to identify an etiology for a C.G.P. has received grant support to develop educational materi- patient’s hearing loss, the possibility of a genetic als on cancer for the Deaf community. H.L.R. is employed by a or acquired etiology remains. This point must be fee-for-service laboratory that offers diagnostic testing for hearing emphasized because it can be misunderstood by cli- loss. The other authors declare no conflict of interest. nicians and by patients and their families. For interested patients and families, further genetic testing References 1. Finitzo T, Albright K, O’Neal J. The newborn with hearing loss: detection in the may be pursued on a research basis. nursery. Pediatrics 1998;102:1452–1460. • Temporal bone imaging by computed tomography or 2. Yoshinaga-Itano C, Coulter D, Thomson V. Developmental outcomes of magnetic resonance imaging should be considered as children with hearing loss born in Colorado hospitals with and without universal newborn hearing screening programs. Semin Neonatol a complement to genetic testing, particularly if the 2001;6:521–529. diagnosis remains unclear, if cochlear implantation 3. American Academy of Audiology Childhood Hearing Screening Guidelines. is being considered, if auditory neuropathy is noted, American Academy of Audiology [serial online] 2012; American Academy of Audiology. http://www.cdc.gov/ncbddd/hearingloss/documents/AAA_ in cases of progressive hearing loss, or if other clini- Childhood%20Hearing%20Guidelines_2011.pdf. Accessed 12 June 2012. cal concerns exist. The anticipated clinical utility of 4. 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Pandya A, Arnos KS, Xia XJ, et al. Frequency and distribution of GJB2 (connexin increases with age. 26) and GJB6 (connexin 30) mutations in a large North American repository of 4. Referral to a multidisciplinary care center, when available, deaf probands. Genet Med 2003;5:295–303. is recommended. 8. National Institute on Deafness and Other Communication Disorders (NIDCD): Presbycusis Health Statistics. National Institute on Deafness and Other • A team approach that includes otolaryngologists, Communication Disorders [serial online] 2011; http://www.nidcd.nih.gov/ clinical geneticists, genetic counselors, audiologists, health/hearing/presbycusis.htm. Accessed 12 June 2012. speech and language specialists, early hearing inter- 9. Carlsson PI, Van Laer L, Borg E, et al. The influence of genetic variation in oxidative stress genes on human noise susceptibility. Hear Res 2005;202:87–96. vention and family support specialists (which may 10. Friedman RA, Van Laer L, Huentelman MJ, et al. 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12. Unal M, Tamer L, Dogruer ZN, Yildirim H, Vayisoglu Y, Camdeviren H. 39. Chan DK, Schrijver I, Chang KW. Connexin-26-associated deafness: N-acetyltransferase 2 gene polymorphism and presbycusis. Laryngoscope phenotypic variability and progression of hearing loss. Genet Med 2005;115:2238–2241. 2010;12:174–181. 13. Van Eyken E, Van Camp G, Van Laer L. The complexity of age-related hearing 40. Kenna MA, Feldman HA, Neault MW, et al. Audiologic phenotype and impairment: contributing environmental and genetic factors. Audiol Neurootol progression in GJB2 (Connexin 26) hearing loss. Arch Otolaryngol Head Neck 2007;12:345–358. Surg 2010;136:81–87. 14. Van Laer L, Van Eyken E, Fransen E, et al. The grainyhead like 2 gene (GRHL2), 41. Norris VW, Arnos KS, Hanks WD, Xia X, Nance WE, Pandya A. Does universal alias TFCP2L3, is associated with age-related hearing impairment. Hum Mol newborn hearing screening identify all children with GJB2 (Connexin 26) Genet 2008;17:159–169. deafness? 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Missense mutations in GJB2 encoding of novel allelic variants of SLC26A4 in non-syndromic hearing loss patients with connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness enlarged vestibular aqueduct in China. PLoS ONE 2012;7:e49984. syndrome. Am J Hum Genet 2002;70:1341–1348. 26. Schultz JM. Waardenburg syndrome. Semin Hear 2006;27:171–181. 52. Pandya A. Nonsyndromic Hearing Loss and Deafness, Mitochondrial. 22 October 27. Madeo AC, Pryor SP, Brewer C et al. Pendred syndrome. Semin Hear 2004 [updated 21 April 2011]. In: Pagon RA, Adam MP, Bird TD, et al. (eds). 2006;27:160–170. GeneReviews [Internet] University of Washington: Seattle, WA, 1993–2014. 28. Bamiou DE, Savy L, O’Mahoney C, Phelps P, Sirimanna T. Unilateral sensorineural http://www.ncbi.nlm.nih.gov/books/NBK1422. Accessed 7 February 2014. hearing loss and its aetiology in childhood: the contribution of computerised 53. Estivill X, Govea N, Barceló E, et al. 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Congenital cytomegalovirus (CMV) infection 34. Estivill X, Fortina P, Surrey S, et al. Connexin-26 mutations in sporadic and as a cause of permanent bilateral hearing loss: a quantitative assessment. J Clin inherited sensorineural deafness. Lancet 1998;351:394–398. Virol 2008;41:57–62. 35. Kelsell DP, Dunlop J, Stevens HP, et al. Connexin 26 mutations in hereditary non- 60. Dollard SC, Grosse SD, Ross DS. New estimates of the prevalence of neurological syndromic sensorineural deafness. Nature 1997;387:80–83. and sensory sequelae and mortality associated with congenital cytomegalovirus 36. Kenneson A, Van Naarden Braun K, Boyle C. GJB2 (connexin 26) variants infection. Rev Med Virol 2007;17:355–363. and nonsyndromic sensorineural hearing loss: a HuGE review. Genet Med 61. Yamamoto AY, Mussi-Pinhata MM, Isaac Mde L, et al. Congenital 2002;4:258–274. cytomegalovirus infection as a cause of sensorineural hearing loss in a highly 37. Kudo T, Ikeda K, Kure S, et al. 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Genetics in medicine | Volume 16 | Number 4 | April 2014 355 Review Article

Neurodevelopmental Manifestations of Mitochondrial Disease Marni J. Falk, MD

ABSTRACT: Mitochondrial disease is an increasingly recognized but widely heterogeneous group of multisystemic disorders that commonly involve severe neurodevelopmental manifestations in childhood. This review explores the presentation, genetic basis, and diagnostic evaluation of primary mitochondrial disease. Empha- sis is placed on neurodevelopmental findings that may be encountered by a Developmental Pediatrician that should provoke consideration of a mitochondrial disorder. The inheritance patterns and mechanisms by which mutations in genes located in either the nuclear or mitochondrial genomes can cause mitochondrial diseases are discussed. A general overview of the current diagnostic evaluation that can be readily initiated by the Developmental Pediatrician is provided, along with a summary of currently available treatment options. (J Dev Behav Pediatr 31:610–621, 2010) Index terms: OXPHOS, mfDNA, nDNA, mitochondrial disease diagnosis.

OVERVIEW OF HUMAN MITOCHONDRIAL high-energy demand tissues.15 Indeed, clinical problems DISEASE involving three or more systems should invoke consid- A recent development in the world of inherited dis- eration of mitochondrial disease into the differential di- ease has been the realization that dysfunction of the agnosis. Typical sequelae of RC dysfunction may involve mitochondrial respiratory chain constitutes a frequent almost any system: neurologic (central, peripheral, or group of disorders that afflict all ages and ethnicities.1,2 autonomic nervous systems), heart (arrhythmias, cardio- Indeed, mutations in hundreds of discrete genes—orig- myopathy), skeletal muscle (myopathy), eyes (eye move- inating in either nuclear (nDNA) or mitochondrial ment abnormalities, vision loss due to retinal or optic (mtDNA) genomes—culminate in energy deficiency and nerve disease, ptosis), endocrine organs (diabetes melli- organ failure. The five-complex respiratory chain (RC), tus, hypothyroidism, hypoparathyroidism, growth hor- also known as the electron transport chain, is the site of mone deficiency, adrenal insufficiency), kidneys (renal oxidative phosphorylation (OXPHOS) within the inner tubular acidosis, aminoaciduria, nephropathy), gastroin- mitochondrial membrane in which the end products of testinal tract (liver failure, dysmotility), hearing (sen- intermediary metabolism are oxidized to generate en- sorineural hearing loss, vestibular dysfunction), ergy in the form of adenosine triphosphate. Primary and/or may cause global metabolic instability with mitochondrial disease refers to disorders whose under- susceptibility to infections and other catabolic stres- lying genetic cause directly impairs RC composition or sors.15 Each gene, and even mutation, implies a differ- function. Secondary OXPHOS dysfunction, by contrast, ent disorder, hence the extensive variability in mani- has been described in a host of other genetic or envi- festations, prognosis, and inheritance characteristic of ronmental disorders, including other genetic disorders “mitochondrial disease.”16,17 (i.e., Rett syndrome,3 other metabolic defects,4–7 chromosomal aneuploidies,8,9) or toxicities from drugs (i.e., NEURODEVELOPMENTAL MANIFESTATIONS OF valproate,10 statins,11 pesticides12,13). The minimal prev- MITOCHONDRIAL DISEASE alence of primary mitochondrial disease is one in Neurologic “Red-Flag” and “Nonspecific” Findings in 5000,1,2 although pathogenic mutations in mitochondrial Mitochondrial Disease DNA (mtDNA) may occur as frequently as one in 200 Neurodevelopmental abnormalities are common in births.14 primary mitochondrial disease and may present at any Primary RC (OXPHOS) dysfunction is commonly char- age. Table 1 lists both red flag neurologic findings that acterized by progressive, multisystemic involvement of may present in infants and children with primary mitochondrial disease15 and a wide range of nonspecific

From the Division of Human Genetics, Department of Pediatrics, The Children’s neurologic findings that often occur in combination in Hospital of Philadelphia and University of Pennsylvania School of Medicine, mitochondrial disease. By definition, nonspecific presen- Philadelphia, PA. tations also lead to a wide range of other primary diag- Received March 2010; accepted May 2010. noses. Axonal neuropathy and/or autonomic nervous Address for reprints: Marni J. Falk, MD, The Children’s Hospital of Philadelphia, system involvement may occur in mitochondrial disease, ARC 1002c, 3615 Civic Center Blvd, Philadelphia, PA 19104; e-mail: [email protected]. although these presentations are more commonly diagnosed in older children and adults. Sensorineural hearing Copyright © 2010 Lippincott Williams & Wilkins loss is a common finding that occurs in a wide range of

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