Genetic Carrier Screening

Test Indications Carrier screening is a significant testing tool for inherited genetic beta-lipoproteins causes the associated nutritional and neurological conditions of prenatal care. The purpose of carrier screening is to problems in people with abetalipoproteinemia. identify couples at-risk for passing on genetic conditions to their Abetalipoproteinemia has been reported in approximately offspring. The Genetic Carrier Screening Ashkenazi Jewish Panel 100 cases worldwide. provides not only the currently recommended carrier screening tests, but also other important high-risk inherited genetic conditions. Alport syndrome: Also known as Collagen type IV alpha 3 (COL4A3), Identification of a pathogenic variant in one of these genes, or variants gene-related Alport syndrome has either autosomal recessive in genes associated with 43 high-risk diseases, can help health care or dominant inheritance. This condition is featured by kidney providers and genetic counselors who wish to establish or confirm a malfunction, hearing loss, and eye abnormalities. diagnosis, predict the risk of having a child with a genetic disorder, or to guide patients’ management decisions. Pathogenic variants of the COL4A3 gene encoding type IV collagen prevent the kidneys from filtering the blood properly, blocks Considerations for Testing transformation of sound waves into nerve impulses to the brain, and fails to maintain the shape of the lens and the normal color of the A health care provider or genetic counselor may determine if an retina. individual is at-risk to have offspring with a genetic disorder by obtaining a family health history. The Carrier screening test should be offered if: Worldwide, Alport syndrome occurs in approximately 1 in 50,000 newborns, and is estimated to affect approximately 1 in 5,000-10,000 • an individual has a genetic disorder. people in the general population in the United States. • an individual has a child who has a genetic disease. Arthrogryposis, Mental Retardation and Seizures (AMRS) is an • an individual has a family history of a genetic disorder. autosomal recessive inherited disorder where newborns have • an individual belongs to an ethnic group that has a high carrier multiple joint contractures in their arms or legs. Affected infants rate of genetic disorders (e.g., Ashkenazi Jewish heritage). may have limb malformations, hypotonia, and microcephaly. Furthermore, The American College of Obstetricians and Gynecologists Children with AMRS typically develop intellectual disability, autistic (ACOG) recommends that carrier screening for cystic fibrosis should be characteristics, as well as seizures. offered to all women who are considering pregnancy or are currently ARMS is caused by genetic changes in the solute carrier family 35 pregnant (2). member A3 (SLC35A3) gene, which encodes a transporter found in If a patient considering pregnancy is determined to be a carrier, testing the Golgi apparatus membrane. is also recommended for their partner. AMRS is a rare disorder, which is seen more commonly in those of Genetics Ashkenazi Jewish descent, where it has a 1 in 453 carrier frequency. The conditions listed in Table 1 can be caused by inherited genetic Bardet-Biedl Syndrome is an autosomal recessive disorder variants. The variants are inherited in an autosomal recessive pattern characterized by severe pigmentary retinopathy, obesity, in which a gene variant is a recessive gene located on one of the polydactyly, renal malformation and mental retardation. non-sex chromosomes (non-X and non-Y), or autosomes. One needs Pathogenic variants of the Bardet-Biedl syndrome (BBS) genes are to inherit both copies of the pathogenic gene variant to be affected responsible for this disorder. Most cases of Bardet-Biedl syndrome by the associated disorder. Autosomal recessive disorders are usually result from pathogenic variations in BBS1, BBS2, and BBS10. The passed by two carriers, or individuals whose health is rarely affected BBS genes are involved in cell movement and various chemical but have one variant and one normal copy of the recessive gene. Two signaling pathways. They are also necessary for the perception of carriers have a 25% chance of having an affected child. sensory input. Clinical Characteristics Bardet-Biedl syndrome has a prevalence of 1 in 140,000 to 1 in 160,000 in newborns in most of North America and Europe. It is more Abetalipoproteinemia is an autosomal recessive inherited disorder common on the island of Newfoundland, Canada (1 in 17,000 that affects the absorption of dietary fats, cholesterol, and fat-soluble newborns), and the Kuwait Bedouin population, affecting 1 in 13,500 vitamins. Patients with abetalipoproteinemia are unable to produce newborns. certain lipoproteins that help carry fats and fat-like substances in the blood. Symptoms including failure to gain weight and thrive, and Bloom Syndrome is an inherited condition following an autosomal occur in the first few months of life. Malfunctions of the nervous system recessive pattern. Patients with this condition are characterized by and eye disorders may develop later in childhood. short stature, a skin rash that develops after exposure to the sun, and a greatly increased risk of cancer. Others features may appear in Pathogenic variants of the microsomal triglyceride transfer protein patients, including learning disabilities, a high risk of diabetes, chronic (MTTP) gene fail to produce beta-lipoproteins which are necessary for the absorption of fats and fat-like substances from the diet. A lack of 1 Medical Diagnostic Laboratories, L.L.C. • www.mdlab.com • 877.269.0090 Upd: 5/2018 Table 1. MDL’s Genetic Carrier Screening Ashkenazi Panel Detected Diseases, Target Genes and Frequencies. Carrier Frequency- The chance of an individual with no symptoms having a disease-causing variant. Detection Rate- The percentage of carriers calculated to be detected by the Genetic Carrier Screening test. Residual Risk- The chance of being a carrier even if an individual is found negative for the disease-causing variants tested. Carrier Detection Disease Gene Population Frequency Rate Residual Risk Ashkenazi 1 in 186 75% 1 in 744 Abetalipoproteinemia MTTP General <1 in 500 10% 1 in 556 Ashkenazi 1 in 192 48% 1 in 369 Alport Syndrome, COL4A3-related COL4A3 General 1 in 354 44% 1 in 632 Ashkenazi 1 in 453 95% 1 in 9,060 Arthrogryposis, Mental Retardation, and Seizures (AMRS) SLC35A3 General <1 in 500 95% 1 in 10,000 Bardet-Biedl Syndrome, BBS1-related BBS1 General 1 in 392 70% 1 in 1,307 Ashkenazi 1 in 140 95% 1 in 2,800 Bardet-Biedl Syndrome, BBS2-related BBS2 General <1 in 500 29% 1 in 704 Bardet-Biedl Syndrome, BBS10-related BBS10 General 1 in 423 46% 1 in 783 Ashkenazi 1 in 134 97% 1 in 4,466 ♦ Bloom Syndrome BLM General <1 in 500 10% 1 in 556 Ashkenazi 1 in 55 99% 1 in 5,500 ♦ Canavan Disease ASPA General 1 in 158 53% 1 in 336 Caucasian 1 in 200 70% 1 in 667 Carnitine Palmitoyltransferase II Deficiency CPT2 Ashkenazi 1 in 45 73% 1 in 167 General 1 in 182 65% 1 in 520 Caucasian 1 in 266 82% 1 in 1,478 ♦ Congenital Amegakaryocytic Thrombocytopenia MPL Ashkenazi 1 in 57 95% 1 in 1,140 General 1 in 415 76% 1 in 1,729 Caucassian 1 in 42 77% 1 in 183 Congenital Disorder of Glycosylation Type 1a PMM2 Ashkenazi 1 in 61 89% 1 in 555 General 1 in 124 71% 1 in 428 Caucasian 1 in 25 94% 1 in 417 ♦*Cystic Fibrosis CFTR Asian 1 in 94 65% 1 in 269 Ashkenazi 1 in 24 97% 1 in 800 Ashkenazi 1 in 165 95% 1 in 3,300 Dyskeratosis Congenita, RTEL1-related RTEL1 General <1 in 500 46% 1 in 926 Ashkenazi 1 in 187 96% 1 in 4,675 Ehlers-Danlos Syndrome Type VIIC ADAMTS2 General <1 in 500 80% 1 in 2,500 Ashkenazi 1 in 31 99% 1 in 3,100 ♦ Familial Dysautonomia IKBKAP General <1 in 500 10% 1 in 556 Ashkenazi 1 in 52 97% 1 in 1,733 ♦ Familial Hyperinsulinism: ABCC8-related ABCC8 Finnish 1 in 100 43% 1 in 175 Ashkenazi 1 in 89 99% 1 in 8,900 ♦ Fanconi Anemia Type C FANCC General 1 in 417 30% 1 in 596 Ashkenazi 1 in 58 95% 1 in 1,160 ♦* Fragile X Syndrome FMR1 General 1 in 250 95% 1 in 5,000 Caucasian 1 in 152 80% 1 in 760 ♦ Galactosemia, GALT-related GALT Ashkenazi 1 in 156 80% 1 in 780 General 1 in 112 80% 1 in 560 General 1 in 158 60% 1 in 395 ♦ Gaucher Disease GBA Ashkenazi 1 in 15 95% 1 in 300 Caucasian 1 in 177 69% 1 in 571 ♦ Glycogen Storage Disease 1a G6PC Ashkenazi 1 in 71 99% 1 in 7,100 Ashkenazi 1 in 110 95% 1 in 2,200 Joubert Syndrome 2 TMEM216 General <1 in 500 95% 1 in 10,000 Mennonite 1 in 10 99% 1 in 67 ♦ Maple Syrup Urine Disease Type 1a BCKDHA General 1 in 289 10% 1 in 482 Ashkenazi 1 in 97 99% 1 in 9,700 ♦ Maple Syrup Urine Disease Type 1b BCKDHB General 1 in 327 10% 1 in 363 Ashkenazi 1 in 107 87% 1 in 823 ♦ Maple Syrup Urine Disease Type 3 DLD General <1 in 500 60% 1 in 1,250 Ashkenazi 1 in 89 48% 1 in 171 ♦ Mucolipidosis Type IV MCOLN1 General <1 in 500 10% 1 in 556 Ashkenazi 1 in 279 95% 1 in 5,580 Multiple Sulfatase Deficiency SUMF1 General <1 in 500 18% 1 in 610 Ashkenazi 1 in 168 5% 1 in 177 ♦ Nemaline Myopathy NEB General 1 in 224 10% 1 in 249 Ashkenazi 1 in 115 97% 1 in 3,833 ♦ Niemann-Pick Disease, SMPD1-related SMPD1 General 1 in 196 20% 1 in 491 Ashkenazi 1 in 453 95% 1 in 9,060 Phosphoglycerate Dehydrogenase Deficiency, PHGDH-related PHGDH General <1 in 500 92% 1 in 6,250 Finland 1 in 70 60% 1 in 175 Polycystic Kidney Disease, Autosomal Recessive PKHD1 Ashkenazi 1 in 106 18% 1 in 129 General 1 in 144 19% 1 in 178 Retinitis Pigmentosa 59 DHDDS Ashkenazi 1 in 117 95% 1 in 2,340 Caucasian 1 in 48 62% 1 in 126 Smith-Lemli-Opitz Syndrome DHCR7 Ashkenazi 1 in 41 81% 1 in 216 General 1 in 68 63% 1 in 184 Ashkenazi 1 in 41 94% 1 in 683 European Caucasian 1 in 354 95% 1 in 700 ♦* Spinal Muscular Atrophy SMN1 Asian 1 in 53 93% 1 in 757 Hispanic 1 in 117 95% 1 in 2,340 French Canadian 1 in 73 47% 1 in 138 ♦ Tay-Sachs Disease HEXA Ashkenazi 1 in 27 98% 1 in 1,350 General 1 in 288 90% 1 in 2,880 French Canadian 1 in 66 95% 1 in 1,320 Tyrosinemia Type 1 FAH Ashkenazi 1 in 143 99% 1 in 14,300 Ashkenazi 1 in 120 95% 1 in 2,400 ♦ Usher Syndrome Type III CLRN1 General 1 in 500 10% 1 in 556 Finnish 1 in 70 10% 1 in 78 Ashkenazi 1 in 78 75% 1 in 312 ♦ Usher Syndrome Type 1F PCDH15 General 1 in 395 10% 1 in 439 Ashkenazi 1 in 80 95% 1 in 1,600 Walker-Warburg syndrome FKTN-related FKTN General <1 in 500 10% 1 in 556 European Caucasian 1 in 90 47% 1 in 170 Wilson Disease ATP7B Ashkenazi 1 in 67 79% 1 in 238 General 1 in 90 53% 1 in 191 Caucasian 1 in 147 70% 1 in 490 Zellweger Spectrum Disorder, PEX1-related PEX1 General <1 in 500 68% 1 in 1,563 Zellweger Spectrum Disorder, PEX2-related PEX2 Ashkenazi 1 in 227 99% 1 in 22,700 General 1 in 280 30% 1 in 400 2 Zellweger Spectrum Disorder, PEX6-related PEX6 French Canadian 1 in 55 95% 1 in 21,620 ♦ Available for order as an individual test. * Included in Test 1274 Genetic Carrier Screening Panel. obstructive pulmonary disease, and mild immune system abnormalities. Congenital amegakaryocytic thrombocytopenia is estimated to Bloom syndrome is caused by pathogenic variants of the bloom occur in 1 in 22,500 pregnancies amongst the Ashkenazi Jewish syndrome RecQ-like helicase (BLM) gene that produces RecQ population, and 1 in 57 of this population are carriers. helicases which maintain the stability of DNA during duplications. Congenital Disorder of Glycosylation Type Ia is also known as Without this helicase, the cell is less able to repair DNA damage PMM2-congenital disorder of glycosylation (PMM2-CDG), and is caused by ultraviolet light, resulting in increased sun sensitivity. Cancers inherited in an autosomal recessive pattern. Signs and symptoms develop from this abnormal DNA repair process leading to cell division of the condition are usually developed during infancy. Affected in an uncontrolled way. infants may have hypotonia, abnormal distribution of fat, Bloom syndrome is a rare disorder. Approximately one-third of people strabismus, developmental delay, and a failure to thrive. with the disease are from Ashkenazi Jewish descent. Roughly 1 in 48,000 Pathogenic variants of the PMM2 gene are responsible for the Ashkenazi Jews are affected by the disease. condition. Without an enzyme called phosphomannomutase 2 Canavan Disease is a rare autosomal recessive inherited disorder (PMM2), encoded from the PMM2 gene, glycosylation cannot be that damages the ability of neurons in the brain to send and receive processed to modify proteins, leading to the symptoms of PMM2- messages. This disrupts the growth or maintenance of the myelin CDG. sheath, which is the covering that protects nerves and promotes PMM2-CDG accounts for 70% of the congenital disorders of the efficient transmission of nerve impulses. Neonatal and infantile glycosylation, which combined affect 1 in 50,000 to 100,000 births. Canavan disease is the most common and most severe form of the condition. Affected infants develop atonia of neck muscles, hypotonia, Cystic Fibrosis (CF) is the most common life-threatening autosomal hyperextension of legs and flexion of arms, blindness, severe mental recessive condition in the non-Hispanic, white population. It defects, megalocephaly, and death by 18 months on the average. is a progressive, multisystem disease that primarily affects the pulmonary, pancreatic, and gastrointestinal systems by the buildup Pathogenic variants of the aspartoacylase (ASPA) gene cause of a thick, sticky mucus that can clot the airways and block the Canavan disease. The ASPA gene contributes making aspartoacylases. intestine and ducts. The current median survival is approximately This enzyme normally breaks down a compound called N-acetyl-L- 37 years, with respiratory failure as the most common cause of aspartic acid (NAA), which is predominantly found in neurons in the death. brain. The enzyme may be involved in the transport of water molecules out of neurons. Pathogenic variants of the ASPA gene reduce the Cystic fibrosis is caused by pathogenic variants of the CF function of aspartoacylase, which prevents the normal breakdown transmembrane regulator (CFTR) gene, which provides instructions of NAA. A buildup of NAA destroys existing myelin sheaths. Nerves for making a channel that transports negatively-charged chloride malfunction without this protective covering, which disrupts normal ions into and out of cells. Pathogenic variants of the CFTR gene brain development. disrupt the function of the chloride channels, preventing the regulation of chloride ions and water across cell membranes. As a While this condition occurs in people of all ethnic backgrounds, it is result, cells that line the passageways of the lungs, pancreas, and most common in people of Ashkenazi Jewish heritage. Studies suggest other organs produce mucus that is unusually thick and sticky. Two that this disorder affects 1 in 6,400 to 13,500 people in the Ashkenazi copies of pathogenic variants of this gene cause CF. Jewish population. Cystic fibrosis is a common genetic disease within the Caucasian Carnitine Palmitoyltransferase II, (CPT II) Deficiency is an autosomal population in the United States. The disease occurs in 1 in 2,500 to recessive condition that prevents the body from processing long- 3,500 white newborns. Cystic fibrosis is less common in other ethnic chain fatty acids into energy, particularly during fasting. Carnitine groups, affecting about 1 in 17,000 African Americans and 1 in palmitoyltransferase (CPT2) gene products are responsible for the 31,000 Asian Americans. long-chain fatty acid breakdown process. The symptoms of the lethal ACOG Recommendation: neonatal form of CPT II deficiency appear after birth and affect various organs including the liver, lungs, heart, kidney, and brain. Affected infants • CF screening is important to be offered to women of die within the first year of life. A severe infantile hepatocardiomuscular reproductive age. It is becoming increasingly difficult to assign form of CPT II deficiency has similar characteristic symptoms as the a single ethnicity to individuals. lethal neonatal form, but these symptoms begin from 2 years of age. • When one member of a couple is a carrier of CF, the other The myopathic form of CPT II deficiency is the most common type. partner should be offered screening. Symptoms can begin at any time from childhood to one’s 60’s. People with this form experience periodic attacks involving their muscles. Dyskeratosis Congenita, RTEL1-related: Dyskeratosis congenita has Worldwide, carnitine palmitoyltransferase II deficiency occurs in three major characteristics, including nail dystrophy, pigmentation, approximately 1 in 10,000 to 1 in 100,000 births. and oral leukoplakia. RTEL1-related Dyskeratosis congenita can be inherited in an autosomal dominant or autosomal recessive Congenital Amegakaryocytic Thrombocytopenia (CAMT) is a pattern. rare inherited autosomal recessive disorder characterized by RTEL1 encodes a DNA helicase implicated in telomere-length thrombocytopenia and an absence of megakaryocytes. It presents regulation, DNA repair, and maintenance of genomic stability. with bleeding recognized on day one of life, or at least within the first This helicase acts as an anti-recombinase to counteract toxic month. recombination and limit crossover during meiosis. Pathogenic Thrombopoeitin (TPO) receptor encoded from the MPL gene is variants of RTEL1 result in a loss of function of DNA repair, leading to essential for the proliferation of megakaryocytes which produce the signs and symptoms of Dyskeratosis congenita. platelets. Pathogenic variants of the MPL gene prevent the production Dyskeratosis congenita has an estimated incidence of of TPO receptors. The absence of platelets leads to the symptoms of approximately 1 in 1,000,000 worldwide. this disorder. Genetic changes in the MPL gene may also result in blood cancers. Ehlers-Danlos Syndrome: More than 10 recognized types of Ehlers-Danlos syndrome have been reported. Among these, the 3 Medical Diagnostic Laboratories, L.L.C. • www.mdlab.com • 877.269.0090 dermatosparaxis Ehlers-Danlos syndrome type VIIC is of autosomal with this condition may develop bone marrow failure, physical recessive inheritance. The dermatosparaxis type of the condition is abnormalities, organ defects, and an increased risk of certain characterized by skin that sags and wrinkles. Redundant folds of skin cancers. Approximately 90% of people with Fanconi anemia may be present as affected children get older. type C have impaired bone marrow function that leads to a A gene called a disintegrin-like and metalloproteinase with decrease in the production of all blood cells. Affected individuals thrombospondin type 1 motif 2 (ADAMTS2) is associated with experience fatigue, frequent infections, and clotting problems. dermatosparaxis Ehlers-Danlos syndrome type VIIC. The ADAMTS2 Another symptom of patients with Fanconi anemia type C is physical abnormalities such as spotted skin or malformations of gene provides instructions for making an enzyme that processes organs. People with this condition are at higher than average risk several types of procollagen molecules. Procollagens are the precursors of collagens, which are complex molecules found in the of cancer development due to the loss of function of proteins that spaces between cells that add strength, support, and elasticity to repair damaged DNA. various body tissues. Pathogenic variants of the ADAMTS2 gene greatly The Fanconi anemia complementation group C (FANCC) gene reduce the production or activity of the ADAMTS2 enzyme. As a result, is one of the critical genes responsible for the Fanconi anemia collagen fibrils are not assembled properly. The resulting fibrils are pathway, which triggers DNA repair processes when DNA damage disorganized, which weakens connective tissues and leads to the signs is detected. Pathogenic variants of the FANCC gene result in either and symptoms of the disorder. abnormal cell death or uncontrolled cell growth due to an inability The dermatosparaxis type is relatively rare among all types of Ehlers- to make new DNA molecules and a lack of the necessary DNA Danlos syndrome. About a dozen infants and children with this repair processes. condition have been reported. Fanconi anemia type C affects approximately 1 in 100,000 people. This condition is more common among people of the Roma Familial Dysautonomia is an autosomal recessive disorder that affects population of Spain, black South Africans, and, especially, those of the development and survival of certain nerve cells. The disorder not Ashkenazi Jewish descent, where 1 in 89 are carriers and 1 in 32,000 only disturbs cells in the autonomic nervous system, which controls have the actual disease. involuntary actions such as digestion, breathing, and the regulation of blood pressure and body temperature, but also affects the sensory Fragile X syndrome is the most common inherited form of mental nervous system, which controls activities related to the senses, such as impairment. The syndrome is inherited in an X-linked dominant taste and the perception of pain, heat, and cold. pattern and occurs in approximately 1 in 3,600 males and 1 in 4,000–6,000 females of various ethnicities. Fragile X syndrome- Familial dysautonomia is caused by pathogenic variants of the related impairment ranges from borderline, including learning inhibitor of the kappa light polypeptide gene enhancer in B-cells, disabilities, to severe, presenting with cognitive and behavioral kinase complex-associated protein (IKBKAP) gene, which is responsible disabilities, including autism. Signs of Fragile X syndrome are for production of IκB kinase complex-associated protein (IKAP). This subtle in newborns, making Fragile X syndrome difficult to protein is found in a variety of cells throughout the body, including diagnose based on clinical findings alone. brain cells. IKAP plays a key role in transcription of proteins that affect the cell’s cytoskeleton and cell motility. Critical activities in brain cells Fragile X syndrome is caused by expansion of a repeated are probably disrupted by reduced amounts or the absence of IKAP trinucleotide segment of DNA, cytosine–guanine–guanine protein, leading to the signs and symptoms of familial dysautonomia. (CGG), that leads to altered transcription of the Fragile X Familial dysautonomia occurs primarily in people of Ashkenazi Jewish mental retardation 1 (FMR1) gene. The FMR1 gene provides descent. It affects about 1 in 3,700 individuals in Ashkenazi Jewish instructions for making a protein called FMRP, that helps populations. Familial dysautonomia is rare in the general population. regulate the production of other proteins and plays a role in the development of synapses, which are specialized connections Familial Hyperinsulinism can be an autosomal recessive or dominant between nerve cells. A person with less than 45 repeats is inherited condition in which the pancreas releases inappropriately regarded as unaffected. When more than 200 repeats are large quantities of hormone insulin, leading to hypoglycemia. When present, an individual is said to have a full mutation resulting blood sugar drops to dangerously low levels, seizures and permanent in the full manifestation of Fragile X syndrome. This condition brain damage may occur. causes the FMR1 gene to become methylated. Pathogenic variants of the ATP binding cassette subfamily C member ACOG Recommendation: 8 (ABCC8) gene are the most common cause of the disorder and account for approximately 40% of affected individuals. Pathogenic Genetic counseling and fragile X syndrome carrier screening is variants of the ABCC8 gene lead to over-secretion of insulin from recommended testing to the following: pancreatic beta cells, resulting in glucose being rapidly removed from the bloodstream. A lack of glucose in the blood causes frequent states • Women with a family history of Fragile X-related of hypoglycemia in people with familial hyperinsulinism. disorders, unexplained mental retardation or Familial hyperinsulinism affects roughly 1 in 50,000 Europeans. It is developmental delay, autism, or premature ovarian particularly common among people of Finnish and Saudi Arabian insufficiency are candidates for genetic counseling descent, where the disease may affect as many as 1 in 2,500. and Fragile X carrier screening. Approximately 97% of cases of familial hyperinsulinism in the Ashkenazi • If a woman has ovarian insufficiency or failure or an Jewish population can be attributed to two ABCC8 founder variants elevated follicle-stimulating hormone level before age (p.Phe1387del and c.3989-9G>A). Two additional founder variants in 40 without a known cause, Fragile X carrier screening the ABCC8 gene (p.Val187Asp and p.Glu1506Lys) have been identified should be considered. in the Finnish population. • Women who request Fragile X carrier screening, Fanconi Anemia Type C: Iherited in an autosomal recessive pattern, regardless of family history, should be offered FMR1 Fanconi Anermia Type C is a condition in which the body cannot DNA genetic analysis after genetic counseling about properly produce a protein that protects DNA from damage. People the risks, benefits, and limitations of screening. • All identified carriers of a Fragile X pre-mutation4 (or Medical Diagnostic Laboratories, L.L.C. • www.mdlab.com • 877.269.0090 full mutation) should be referred for follow-up genetic Maple Syrup Urine Disease is an autosomal recessive disorder counseling to discuss the risk to their fetuses of inheriting characterized by a distinctive sweet odor of urine in affected infants. an expanded full mutation Fragile X allele and to discuss Additional symptoms include poor feeding, vomiting, lethargy, and Fragile X associated disorders (premature ovarian developmental retardation. insufficiency and Fragile X tremor ataxia syndrome). Malfunction of a protein complex called branched-chain alpha- Prenatal and preimplantation diagnoses and donor keto acid dehydrogenase, or BCKD, causes maple syrup urine eggs should be discussed. disease. This complex functions to break down amino acids and produce molecules that can be used for energy. BCKD is produced Galactosemia is a disorder that prevents the effective breakdown from branched-chain keto acid dehydrogenase E1, alpha and beta of galactose and energy production. Affected infants fail to gain weight and thrive. They may also develop jaundice, lethargy, liver polypeptides (BCKDHA, and BCKDHB) genes. Pathogenic variants damage, and abnormal bleeding. Affected children may also have in these genes cause accumulation of amino acids (leucine, delayed development, intellectual disability, and vision abnormality. isoleucine, and valine) and their byproducts, leading to serious health problems, known as maple syrup urine disease type Ia and Genetic changes of the galactose-1-phosphate uridylyltransferase Ib. Pathogenic variants of the third component dihydrolipoamide (GALT) gene affect the activity of an enzyme encoded from it, which dehydrogenase (DLD) cause maple syrup urine disease type III, leads to the signs and symptoms of this disorder. referred to as dihydrolipoamide dehydrogenase deficiency. Galactosemia affects 1 in 30,000 to 60,000 newborns. Maple syrup urine disease type Ia and Ib affects 1 in 185,000 infants in the general population. It is most common among the Old Order Gaucher Disease is an autosomal recessive disorder. The signs and Mennonite population, where about 1 in 385 infants are affected symptoms of this condition vary widely among affected individuals by the disease. Type Ia and Ib are also common among Ashkenazi including anemia, thrombocytopenia, bone abnormalities, Jews, with roughly 1 in 50,000 people, and 1 in 35,000 to 48,000 brain damage, skin abnormalities, heart problems, and individuals in type III. hepatosplenomegaly. Gaucher disease is caused by pathogenic variants of the Mucolipidosis Type IV is a rare autosomal recessive inherited glucosylceramidase beta (GBA) gene, which produces an enzyme condition that affects the development of the nerves. It also causes called beta-glucocerebrosidase. This enzyme breaks down the fatty existing nerves to degenerate. Patients with mucolipidosis type IV substance glucocerebroside into glucose. Pathogenic variants of show delayed development in mental and motor skills. Affected the GBA gene greatly decrease or eliminate the activity of beta- infants and children are unable to sit up, crawl, walk or speak glucocerebrosidase. As a result, glucocerebroside can accumulate properly. Mucolipidosis type IV also leads to poor vision caused by to toxic levels within cells, causing the characteristic features of cloudy corneas and degeneration of the retina. Gaucher disease. Mucolipin 1 protein, produced by the mucolipin 1 (MCOLN1) gene, is Gaucher disease occurs in 1 in 50,000 to 100,000 people in the located in the membranes of lysosomes and endosomes and plays general population. The Type 1 non-neuronopathic form is the most a role in trafficking lipids and proteins within the cell. Pathogenic common form of the disorder and occurs more frequently in those of variants in the MCOLN1 gene cause the accumulation of these Ashkenazi Jewish heritage from 1 in 500 to 1,000 people, with 1 in 15 substances in lysosomes, leading to the symptoms of mucolipidosis of this population as carriers. type IV. Glycogen storage disease type I is an autosomal recessive inherited Mucolipidosis type IV is estimated to occur in 1 in 40,000 people. disorder characterized by the accumulation of glycogen that, in turn, About 70% of affected individuals have Ashkenazi Jewish ancestry. It impairs the normal function of certain organs and tissues, especially is reported that roughly 1 in 89 Ashkenazi Jews are carriers. the liver and kidneys. Symptoms typically occur around the age of 3 months, when babies start to sleep through the night and do not Multiple Sulfatase Deficiencyis a condition inherited in an autosomal eat as frequently as newborns. Infants with the condition may have recessive manner with signs and symptoms occurring from birth to hypoglycemia which can lead to seizures. Patients can also develop young adulthood. Affected individuals have deterioration of tissue hyperuricemia and hyperlipidemia. in the nervous system, causing developmental delays, movement problems, and slow growth. Pathogenic variants of the glucose-6-phosphatase catalytic (G6PC) Pathogenic variants in the sulfatase modifying factor 1 (SUMF1) gene gene prevent the effective breakdown of glucose-6-phosphate, leading to glycogen accumulation within cells. A buildup of excessive contribute to the disorder. The SUMF1 gene produces formylglycine- glycogen causes the symptoms of glycogen storage disease Type I. generating enzyme (FGE) that functions in protein modification. Malfunction of FGE leads to cell death, especially in the brain, The overall incidence of glycogen storage disease Type I is 1 in skeleton and skin, causing the symptoms of multiple sulfatase 100,000 people. Approximately 1 in every 20,000 to 25,000 babies in deficiency. the U.S. and Europe are born with glycogen storage disease. Multiple sulfatase deficiency affects approximately 1 per million Joubert Syndrome 2 is an autosomal recessive disorder characterized individuals worldwide. by a specific hindbrain malformation, hypotonia, developmental delay, oculomotor apraxia, and breathing abnormalities that occur Nemaline Myopathy is usually inherited in an autosomal recessive from infancy to early childhood. Additional characteristic features pattern but sometimes in an autosomal dominant pattern. This include retinal anomalies, polydactyly, hepatic fibrosis, and renal disorder results from a lack of nebulin protein encoded by the NEB disease. This disorder is associated with pathogenic variants of the gene. Nebulin plays a significant role in generating the mechanical transmembrane protein 216 (TMEM216) gene. force needed for muscle contraction. People with nemaline myopathy have muscle weakness. They have difficulties in feeding Joubert Syndromes are estimated to occur in between 1 in 80,000 and swallowing during infancy. As the condition progresses, the and 1 in 100,000 births. However, Joubert Syndromes have a large breathing muscles are affected and may lead to a lethal condition. range of possible manifestations and are likely underdiagnosed. Nemaline myopathy has an estimated incidence of 1 in 50,000 in the general population. 5 Medical Diagnostic Laboratories, L.L.C. • www.mdlab.com • 877.269.0090 Niemann-Pick Disease is an autosomal recessive inherited condition Smith-Lemli-Opitz Syndrome, or SLO syndrome, is an autosomal which is divided into four types. Among them, type A and type B are recessive inherited developmental disorder in which the body loses the most common. Infants and children with Niemann-Pick disease the ability to make sufficient cholesterol due to pathogenic variations type A usually develop hepatosplenomegaly, respiratory failure, in the 7-dehydrocholesterol reductase (DHCR7) gene. The features mental and physical disabilities, and eye abnormalities. Niemann- of this disorder vary widely, including microcephaly, intellectual Pick disease type B, whose symptoms are similar to, but not as severe disability, malformation of various organs, muscle hypotonia, and as type A, usually present in mid-childhood. syndactyly and polydactyly. Niemann-Pick disease types A and B are caused by pathogenic Smith-Lemli-Opitz syndrome affects roughly 1 in 20,000 to 60,000 variants of the sphingomyelin phosphodiesterase 1 (SMPD1) gene. newborns. This condition is most common in Caucasians of European This gene produces an enzyme called acid sphingomyelinase ancestry, particularly people from Central European countries such which localizes to lysosomes. This enzyme is responsible for breaking as Slovakia and the Czech Republic. Smith-Lemli-Opitz syndrome is down lipid molecules. Pathogenic variants in SMPD1 in people with very rare among African and Asian populations. Niemann-Pick disease types A and type B cause lipid accumulation Spinal Muscular Atrophy (SMA) is an autosomal recessive in cells leading to cellular malfunction and death. This leads to a loss neurodegenerative disease that results from the degeneration of of function of various tissues and organs including the brain, lungs, spinal cord motor neurons leading to atrophy of skeletal muscle spleen and liver. and overall weakness. Affected children have a deficiency in Niemann-Pick disease type A and type B affect 1 in 250,000 in the movement, possibly requiring wheelchair assistance. A frequent general population. The incidence within the Ashkenazi population is cause of death of patients with SMA is respiratory failure. There is roughly 1 in 40,000 individuals. no effective treatment for the disease.

Phosphoglycerate Dehydrogenase Deficiency is a condition The disorder is caused by a variation in the survival motor neuron characterized by microcephaly, impaired movements and recurrent gene (SMN1), which is responsible for the production of a protein seizures. It follows an autosomal recessive pattern of genetic essential to motor neurons. More than 98% of patients with SMA inheritance. have an abnormality in both copies of the SMN1 gene, causing a deletion or other pathogenic variation. Pathogenic variants of the phosphoglycerate dehydrogenase The occurrence of SMA is approximately 1 in 10,000 live births and (PHGDH) gene are responsible for the disorder. The PHGDH gene it is reported to be the leading genetic cause of infant death. encodes an enzyme that is involved in the production of serine, which is essential for the development and function of the brain ACOG Recommendations: and spinal cord. Pathogenic variants of the PHGDH gene affect the Genetic counseling and SMA carrier screening should be offered enzyme by decreasing its activity. As a consequence, the formation to the following patients or couples: of myelin and the production of neurotransmitters in the brain can be impaired. • Those with a family history SMA or SMA-like disease Phosphoglycerate dehydrogenase deficiency is a rare disorder. Only Those who request SMA carrier screening and have completed 15 cases have been reported in the scientific literature. genetic counseling that included discussion of the sensitivity, specificity, and limitations of screening. Polycystic Kidney Disease, Autosomal Recessive, PKHD1-Related: Patients with polycystic kidney disease always develop clusters of Tay-Sachs Disease (TSD) is inherited in an autosomal recessive fluid-filled sacs (cysts) in the kidneys and their ability to filter waste pattern, and is a lysosomal storage disease in which GM2 products from the blood is impaired. Frequent complications of gangliosides accumulate throughout the body. The accumulation polycystic kidney disease include severe hypertension, hematuria, of these gangliosides in the central nervous system results in a severe recurrent urinary tract infections, kidney stones, and heart valve progressive destruction of nerve cells in the brain and spinal cord that abnormalities. The signs and symptoms of this condition are usually causes death in early childhood. Affected infants lose motor skills apparent at birth or in early infancy. such as turning over and sitting. Along with the progression, patients Pathogenic variants of the PKHD1 gene are related to polycystic experience seizures, vision and hearing loss, and intellectual disability. kidney disease. This gene encodes fibrocystin that is involved in Pathogenic variants of the HEXA gene disrupt the activity of beta- various cellular signaling pathways, cellular adhesion, and cellular hexosaminidase A, which prevents the enzyme from breaking down proliferation. GM2 ganglioside. As a result, this substance accumulates to toxic PKHD1-related autosomal recessive polycystic kidney disease occurs levels, particularly in neurons in the brain and spinal cord. in an estimated 1 in 20,000 to 40,000 people worldwide. The TSD carrier rate in Jewish individuals of Eastern European descent (Ashkenazi) is 1 in 29; the carrier rate for non-Jewish individuals is 1 Retinitis pigmentosa: Pathogenic variants of the dehydrodolichyl in 288. It has been determined that individuals of French–Canadian diphosphate synthase (DHDDS) gene are responsible for retinitis and Cajun descent also have a greater carrier frequency than the pigmentosa disorder, which is an autosomal recessive inheritance. general population. In people with this condition, vision loss occurs as the light-sensing cells of the retina gradually deteriorate. A loss of night vision usually ACOG Recommendations: appears as the first symptom in childhood. Later, this disease causes • Screening for TSD should be offered before pregnancy if both blind spots in the peripheral vision. Over time, the disease progresses members of a couple are of Ashkenazi Jewish, French–Canadian, and eventually affects central vision. In adulthood, many people or Cajun descent. Those with a family history consistent with TSD with this condition become blind. also should be offered screening. Retinitis pigmentosa is one of the most common inherited diseases of • When one member of a couple is at high-risk (i.e., of Ashkenazi the retina. It occurs in 1 in 3,500 to 4,000 people in the United States Jewish, French–Canadian, or Cajun descent or has a family and Europe. history consistent with TSD), but the other partner is not, the high-risk partner should be offered screening. This is particularly important if there is uncertainty about ancestry or if there is a family history 6 Medical Diagnostic Laboratories, L.L.C. • www.mdlab.com • 877.269.0090 consistent with TSD. If the high-risk partner is determined to be a problems. The most characteristic symptom of patients with Wilson carrier, the other partner should also be offered screening. If the disease is the Kayser-Fleischer ring, which surrounds the colored woman is already pregnant, it may be necessary to offer screening part of the eye resulting from a copper deposit in the front surface to both partners simultaneously to ensure that results are obtained of the cornea. Abnormalities in eye movements may also occur. promptly and that all options are available to the couple. Wilson disease is caused by pathogenic variants of the ATPase • If TSD biochemical screening is performed in women who are copper-transporting beta polypeptide (ATP7B) gene that encodes pregnant or taking oral contraceptives, leukocyte testing must be a polypeptide that acts as a plasma membrane copper-transport used. protein. Malfunction of this protein leads to copper accumulation in the body to a toxic level causing damage to tissues and organs. • If both partners are determined to be carriers of TSD, genetic counseling and prenatal diagnosis should be offered. Approximately 1 in 30,000 people have Wilson disease worldwide. It is most common in China, Japan, and Sardinia, where it may affect Tyrosinemia type 1 is an autosomal recessive inherited metabolic as many as 1 in 10,000 people. disorder characterized by disruptions in the process that breaks down tyrosine. Accumulation of tyrosine and its byproducts in tissues and Zellweger Spectrum Disorder includes Zellweger syndrome, organs can cause severe symptoms. Affected infants fail to gain weight neonatal adrenoleukodystrophy (NALD) and infantile Refsum and thrive. They may also develop jaundice. disease. Zellweger syndrome is inherited in an autosomal recessive This condition is caused by pathogenic variations of the pattern. Individuals with Zellweger syndrome, the most severe form fumarylacetoacetate hydrolase (FAH) gene, which produces an of the spectrum, develop signs and symptoms during the newborn enzyme involved in the last step of the catabolic pathway of tyrosine. period. These infants experience hypotonia, feeding problems, hearing and vision loss, and seizures. These problems are caused Tyrosinemia type I affects about 1 in 100,000 individuals in the general by the breakdown of myelin, which is the covering that protects population. It is more common in Norway where 1 in 60,000 to 74,000 nerves and promotes the efficient transmission of nerve impulses. individuals are affected. This disease is even more common in Quebec, People with NALD or infantile Refsum disease, the less severe form Canada where it occurs in about 1 in 16,000 people. of the spectrum, usually do not develop signs and symptoms until late infancy. They may have similar characteristics as Zellweger Usher Syndrome is a condition of autosomal recessive inheritance syndrome, but their condition progresses more slowly. characterized by partial or total hearing and vision loss that worsens over time. Individuals with Usher syndrome type 1F are born with severe Zellweger spectrum disorder is caused by pathogenic variations hearing loss. Progressive vision loss becomes apparent in childhood. in a group of genes which provide instructions for production of Children with this condition have difficulty in balance resulting from peroxins. These proteins are essential for the generation of lipids vestibular abnormalities. Different from type 1F, people with Usher used in the nervous system. Pathogenic variants of the PEX1 gene syndrome type 3 have normal hearing at birth, but experience hearing are the most common cause of Zellweger spectrum disorder and and vision loss later in life. are found in nearly 70% of affected individuals. The protocadherin 15 (PCKH15) gene was found to contribute to Usher Zellweger spectrum disorder is estimated to occur in 1 in 50,000 syndrome type 1F, while the clarin 1 (CLRN1) gene is associated with individuals worldwide. Usher syndrome type 3. Both of these genes are involved in normal hearing, balance, and vision. Test Methodology Usher syndrome is estimated to affect 1 in 20,000 people. Usher syndrome Genomic DNA is extracted from a blood, mouthwash, OneSwab® or type 3 occurs more frequently in the Finnish population, where it ThinPrep® sample. High-throughput Next Generation Sequencing is accounts for about 40% of cases. Usher syndrome type 1F occurs more performed to examine over 1,300 DNA variants associated with 41 frequently in the Ashkenazi Jewish population, where approximately 1 diseases. Some pathogenic variants are more severe than others. in 50 people are carriers. This disorder is also the leading cause of deaf- These variant regions are sequenced to high coverage and the blindness among the Jewish population. sequences are compared to standards and references of normal variation. All the reported variants are confirmed by the “gold Walker-Warburg Syndrome is an autosomal recessive inherited standard” Sanger sequencing. In addition, some of the variants condition characterized by symptoms of muscle weakness, vision in the panel may be partially subjected to Sanger sequencing to impairment, brain structure abnormalities, and severe developmental ensure adequate sequencing. delay. FXS methodology: The MDL Fragile X Syndrome testing was Pathogenic variants of the fukutin (FKTN) gene account for this disorder. designed to provide accurate sizing of alleles up to 200 FKTN encodes the fukutin protein which helps to anchor the structural framework of the cytoskeleton and extracellular matrix. It also helps CGG, identification of full mutation alleles >200 CGG anda stabilize muscle fibers in skeletal muscles and direct migration of characteristic product peak profile that resolves zygosity in neurons in the brain. female samples. The MDL Fragile X Syndrome testing uses a regular gene specific PCR and a Triplet Repeat-Primed PCR Walker-Warburg syndrome is estimated to affect 1 in 60,500 newborns worldwide. Approximately 1 in 150 individuals of Ashkenazi Jewish (TRP PCR) from purified genomic DNA and fragment sizing on descent are carriers. an Applied Biosystems Genetic Analyzer. Triplet repeat–primed PCR (TRP PCR) allows rapid detection of PCR products formed Wilson Disease is of autosomal recessive inheritance and causes by a chimeric primer binding inside a triplet-repeat region. accumulation of copper within the body. Copper that is retained In TRP PCR for fragile X, one primer is anchored completely in the liver, brain, kidneys and eyes causes tissue damage, organ outside of the CGG repeat region, whereas the other overlaps failure and death. This initial feature of Wilson disease is usually a liver the CGG repeat and the adjacent non-repeated sequence. problem among affected children and young adults, while individuals diagnosed in adulthood often develop nervous system or psychiatric This TRP PCR will increase the amount of full-length product from the largest CGG-repeat allele and in MDL fragile X assay enables accurate sizing of alleles up to 200 CGG repeats. 7 Medical Diagnostic Laboratories, L.L.C. • www.mdlab.com • 877.269.0090 Risk assessment and clinical interpretation of FXS and related References disorders are defined by the number of CGG repeats and 1. Azimi M, Schmaus K, Greger V, et al. 2016. Carrier screening by next-generation methylation status of the gene. Based on the number of CGG sequencing: health benefits and cost effectiveness.Mol Genet Genomic Med repeats it is possible to distinguish four types of alleles: unaffected (4)3:292-302. 2. Edwards JG, Feldman G, Goldberg J, et al. 2015. Expanded Carrier Screening in or normal alleles (<=44CGG), intermediate or gray zone(45-54 Reproductive Medicine - Points to Consider: A Joint Statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and CGG), premutation (55-200 CGG) and full mutation (>200 CGG). Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine. Obstet Gynecol 125(3):653-62. SMA methodology: The MDL Spinal Muscular Atrophy test uses 3. German J, Sanz MM, Ciocci S, et al. 2007. Syndrome-causing mutations of the BLM Multiplex Ligation-dependent Probe Amplification (MLPA) gene in persons in the Bloom’s Syndrome Registry. Hum Mutat 28(8):743. technique. The principle of MLPA is based on the amplification 4. James C, Kapoor RR, Ismail D, et al. 2009. The genetic basis of congenital hyperinsulinism. J Med Genet 46(5):289-299. of up to 60 probes, each of which detecting a specific DNA 5. Malfait F, De Paepe A. The Ehlers-Danlos syndrome. Progress in Heritable Soft sequence of approximately 60 nucleotides in length. After Connective Tissue Diseases. Springer Netherlands. 2014: 129-143. 6. Surendran S, Michals-Matalon K, Quast MJ, et al. 2003. Canavan disease: a denaturation of the sample DNA, a mixture of MLPA probes monogenic trait with complex genomic interaction. Mol Genet Metab 80(1):74-80. is added to the sample. Each MLPA probe consists of two 7. Aggarwal A, Bhatt M. 2013. Update on Wilson disease. Int Rev Neurobiol 110:313-348. oligonucleotides that must hybridize to immediately adjacent 8. Beales PL. 2005. Lifting the lid on Pandora’s box: the Bardet-Biedl syndrome. Curr Opin Genet Dev 15(3):315-323. target sequences in order to be ligated into a single probe. 9. Simon E, Flaschker N, Schadewaldt P, et al. 2006. Variant maple syrup urine disease Each probe in an MLPA probe mix has a unique amplicon (MSUD)—the entire spectrum. J Inherit Metab Dis 29(6):716-724. 10. Accurso FJ. 2006. Update in cystic fibrosis 2005. Am J Respir Crit Care Med length, typically ranging between 130-500 nucleotides. During 173(9):944-947. the subsequent PCR reaction, all ligated probes are amplified 11. Saihan Z, Webster AR, Luxon L, et al. 2009. Update on Usher syndrome. Curr Opin simultaneously using the same PCR primer pair. One PCR primer is Neurol 22(1):19-27. 12. Kruegel J, Rubel D, Gross O. 2013. Alport syndrome - insights from basic and clinical fluorescently labelled, enabling the amplification products to be research. Nat Rev Nephrol 9(3):170-178. visualized during fragment separation. The relative height of each 13. Deschauer M, Wieser T, Zierz S. 2005. Muscle carnitine palmitoyltransferase II deficiency: clinical and molecular genetic features and diagnostic aspects.Arch individual probe peak, as compared to the relative probe peak Neurol 62(1):37-41. height in various reference DNA samples, reflects the relative 14. Jira PE, Waterham HR, Wanders RJA, et al. 2003. Smith-Lemli-Opitz Syndrome and the copy number of the corresponding target sequence in the DHCR7 Gene. Ann Hum Genet 67(3):269-280. 15. Daiger SP, Bowne SJ, Sullivan LS. 2007. Perspective on genes and mutations causing sample. Five probes used in the MDL Spinal Muscular Atrophy test retinitis pigmentosa. Arch Ophthalmol 125(2):151-158. detect SMN1 exon 7, SMN1 exon 8, SMN2 Exon 7 and two probes 16. Bergeron A, D’Astous M, Timm DE, et al. 2001. Structural and functional analysis of missense mutations in fumarylacetoacetate hydrolase, the gene deficient in that detect the rare allele of two polymorphisms that may be hereditary tyrosinemia type 1. J Biol Chem 276(18):15225-15231. present in the SMN1 gene. More than 95% of SMA patients show 17. Deakyne JS, Mazin AV. 2011. Fanconi anemia: at the crossroads of DNA repair. Biochem 76(1):36-48. homozygous deletion of at least exon 7 of the SMN1 gene. The 18. Koukoui SD, Chaudhuri A. 2007. Neuroanatomical, molecular genetic, and great majority of SMA carriers can be identified by the presence behavioral correlates of fragile X syndrome. Brain Res Rev 53(1):27-38. 19. Chou JY, Mansfield BC. 2008. Mutations in the glucose-6-phosphatase-α (G6PC) of only a single SMN1 exon 7 copy. gene that cause type Ia glycogen storage disease. Hum Mutat 29(7):921-930. 20. Timson DJ. 2016. The molecular basis of galactosemia - Past, present and future. Variant Classification System: The MDL variant classification system is Gene, 589(2): 133-41. based on the 5-tier system recommendations for the interpretation 21. Beutler E. 2006. Gaucher disease: multiple lessons from a single gene disorder. Acta of sequence variants proposed by the American College of Medical Paediatrica 95(S451):103-109. 22. Fernandes Filho JA, Shapiro BE. 2004. Tay-sachs disease. Arch Neurol 61(9):1466-1468. Genetics and Genomics (ACMG) and complies with the standards 23. Axelrod FB. 2004. Familial dysautonomia. Muscle Nerve 29(3):352-363. and guidelines for the interpretation of sequence variants by ACMG 24. Altarescu G, Sun M, Moore DF, et al. 2002. The neurogenetics of mucolipidosis type and the Association for Molecular Pathology (AMP). To classify each IV. Neurol 59(3):306-313. 25. Ballmaier M, Germeshausen M, Schulze H, et al. 2001. C-mpl mutations are the variant, MDL assigns weight to each piece of available evidence, cause of congenital amegakaryocytic thrombocytopenia. Blood 97(1): 139-146. including literature review, reputable database reports, population 26. Pons V, Rolland C, Nauze M, et al. 2011. A severe form of abetalipoproteinemia caused by new splicing mutations of microsomal triglyceride transfer protein (MTTP). frequencies, and computational evidence and prediction. Hum Mutat 32(7):751-759. 27. Yin X, Pu CQ, Wang Q, et al. 2014. Clinical and pathological features of patients with Any detected variants that are a recognized cause of the disease nemaline myopathy. Molec Med Rep 10(1):175-182. (Pathogenic) will be reported. In addition, variants that have not 28. Braverman NE, D’Agostino MD, MacLean GE. 2013. Peroxisome biogenesis disorders: Biological, clinical and pathophysiological perspectives. Dev Disabil Res Rev previously been established as a recognized cause of disease 17(3):187-196. may be identified. In these cases, only variants classified as “likely” 29. Crane DI, Maxwell MA, Paton BC. 2005. PEX1 mutations in the Zellweger spectrum of pathogenic are reported. Benign variants, likely benign variants and the peroxisome biogenesis disorders. Hum Mutat 26(3):167-175. 30. Krause C, Rosewich H, Thanos M, et al. 2006. Identification of novel mutations in variants of uncertain significance, and variants not directly associated PEX2, PEX6, PEX10, PEX12, and PEX13 in Zellweger spectrum patients. Hum Mutat with the intended disease phenotype are not reported. 27(11):1157-1157. 31. Tabatabaie L, De Koning TJ, Geboers AJJM, et al. 2009. Novel mutations in MDL variant results are reported using numbering and nomenclature 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics. Hum Mutat 30(5):749-756. recommended by the Human Genome Variation Society 32. Adeva M, El-Youssef M, Rossetti S, et al. 2006. Clinical and molecular (HGVS http://hgvs.org). All results are reported in reference to Human characterization defines a broadened spectrum of autosomal recessive polycystic kidney disease (ARPKD). Med 85(1):1-21. Genome 19, Human Build 37. 33. Grünewald, S. 2009. The clinical spectrum of phosphomannomutase 2 deficiency (CDG-Ia). Biochim Biophys Acta - Mol Basis Dis 1792(9):827-834. Turnaround Time 34. Baran I, Nalcaci R, Kocak M. 2010. Dyskeratosis congenita: clinical report and review 14 to 21 days of the literature. Int J Dent Hyg 8(1):68-74. • 35. Edvardson S, Ashikov A, Jalas C, et al. 2013. Mutations in SLC35A3 cause autism spectrum disorder, epilepsy and arthrogryposis. J Med Genet 50(11):733-739. Specimen Requirements 36. Shi L, Webb BD, Birch AH, et al. 2017. Comprehensive population screening in the Ashkenazi Jewish population for recurrent disease-causing variants. Clin Genet 91(4): • Whole Blood (Yellow top tube-ACD A) 599-604. Mouthwash 37. Lorson CL, Hahnen E, Androphy EJ, et al. 1999. A single nucleotide in the SMN gene • regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci • OneSwab® 96(11):6307-6311. • ThinPrep® 38. Dalal PG, Coleman M, Horst M, et al. 2015. Case Report: Genetic analysis and anesthetic management of a child with Niemann-Pick disease Type A. F1000Research 4. 39. Cosma MP, Pepe S, Parenti G, et al. 2004. Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency.Hum Mutat 23(6):576-581. 40. Edvardson S, Shaag A, Zenvirt S, et al. 2010. Joubert syndrome 2 (JBTS2) in Ashkenazi Jews is associated with a TMEM216 mutation. Am J Hum Genet 86(1):93-97. 8 Medical Diagnostic Laboratories, L.L.C. • www.mdlab.com • 877.269.0090