Overview of Genetic Syndromes: Etiology, Physical and Behavioral Phenotypes

Cynthia M. Powell, MD Professor of Pediatrics and Genetics Chief, Division of Pediatric Genetics and Metabolism The University of North Carolina at Chapel Hill Objectives

 Understand etiology and examples of numerical chromosome disorders  Be familiar with some of the more common microdeletion syndromes  Be familiar with the new technique of chromosome microarray and examples of conditions diagnosed with this method  Be familiar with behavioral phenotypes of syndromes discussed How to approach the genetic workup of a child with a developmental or psychiatric disorder  Family history Psychiatric disorders, intellectual disability, birth defects, miscarriages, stillbirths, consanguinity  Cognitive impairment? Yes – more likely to have a chromosome abnormality, microdeletion syndrome, Fragile X syndrome, metabolic disorder  Physical anomalies As clue to underlying syndrome

Importance of the family history as a screening tool in both primary and specialty care settings

 A family history can help you screen and assess risks in patients and families for genetically influenced conditions such as depression, substance abuse, psychoses - as well as for an increasing number of single gene conditions, some of which have available diagnostic testing and therapeutic and preventive measures http://www.genetics.edu.au

•Chromosomes are made up of genes on a string

•Each chromosome contains thousands of genes Down syndrome Most common single, known cause of intellectual disability (~ 1/800 births).

picasaweb.google.com

www.hadsa.org/ 95% of Patients With Down Syndrome Have 3 SEPARATE CHROMOSOME 21s

. 47,XY,+21

How Do Numerical Abnormalities Occur…?

Many are due to chromosome segregation errors during meiosis & mitosis . Nondisjunction (failure of chromosomes to disjoin normally) is the most common known cause of aneuploidy. . Premature Separation of sister chromatids is also known to result in aneuploidy . Both monosomies and trisomies result from nondisjunction & premature centromere division

 Others are due to failed cell division or dispermy . Failed cytokinesis (cell division) during mitosis results in tetraploidy & during meiosis results in triploidy . Fertilization of a normal haploid egg with two sperm (dispermy) Health Supervision

 Developmental delay and hypotonia Delayed milestones Speech delay and language problems Mental retardation – mild (55-70) to moderate (40-55) IQ range on average Refer for Early Intervention Services to include speech, PT, OT Special education Mainstreaming/Inclusion Health Supervision

 Vision problems Stabismus (45%), myopia (70%), nystagmus (35%), blocked tear duct (20%), fine lens opacity (59%), cataracts in adults (30-60%) Refer to ophthalmolgist by 6 months of age Health Supervision

 ENT Hearing loss in 66% Conductive, mixed, sensorineural 60-80% middle ear fluid, most require PE tubes Upper airway obstruction/sleep apnea Hearing screening at birth, if normal, repeat at 6 months and 12 months and then annually Down syndrome Most common single, known cause of mental retardation (~ 1/800 births). See fact sheet.

Typical Facies: • Round face picasaweb.google.com www.hadsa.org/ • Upslanting palpebral fissures, epicanthal folds Figure 10-1, Thompson & Thompson • Flat nasal bridge • Open mouth w/ protruding tongue secondary to hypotonia • Small, dysmorphic low-set ears

Thompson & Thompson “Genetics in Medicine, 7th edition pg 91

Down Syndrome

Low-set, Characteristic Folding

Brushfield Spots Around Iris Margin Short Neck w/ Excess Skin Down Syndrome . Mild-Moderate ID (IQ=30- 60) Early intervention programs .Heart Defects: AVSD, VSD Newborn echo, cardiology eval. . GI: Duodenal atresia, Hirschsprung, pyloric stenosis, TE fistula, omphalocele, annular pancreas, imperforate anus

Short & broad hands w/ transverse . Hip Dislocation crease & 5th finger clinodactyly . Hearing Loss . Vision problems pediatric ophthalmolgist @ 1yr

. Endocrine: hypothyroidism Newborn thyroid screen (rpt @ 6mo, then annually)

. Hematologic: leukemia 15X increase, but overall risk < 1% Wide gap between 1st & 2nd toes, furrow extending along length

Turner Syndrome

Lymphedema, Cystic hygroma

Nuchal fold Lymphedema thickness

Webbed neck, nipples widely spaced, carrying angle Short 4th metacarpals Cardiac Abnormalities Turner Syndrome •Bicuspid aortic valve •Aortic dissection •Coarctation of aorta •Cardiac eval, echo Renal Abnormalities •Horseshoe kidney •Unilateral renal agenesis •Renal ultrasound Short Stature .Avg = 4’7” .Endocrine, growth hormone tx Delayed Puberty •2nd sex characteristics http://members.tripod.com/~TS Magicmom/bianca.html •Hormone replacement Infertility ART possible Hearing Impairment Dr. Catherine Ward, is a geneticist with Turner syndrome at Akron Learning Disabilities Children's Hospital in Akron, Ohio •Spatial perception http://www.ohio.com/multimedia/photo_gall • Intervention programs eries Turner Syndrome

Other Sex Chromosome Variations

 Often no phenotypic abnormalities  IQs generally in normal range  Learning disabilities common  High risk of behavioral and psychiatric problems Sex Chromosome Variations: XYY

 Incidence 1/1000  Normal birth weight and length, above average stature  Hyperactivity, distractibility, temper tantrums, low frustration tolerance, learning Former model turned novelist Annabel Giles, 49, …Annabel's second child, Ted, ten, …was born with XYY syndrome, a disabilities in some chromosomal disorder, and here she provides, with extraordinary candour, an account of her life as the single parent of a special needs child.  Wide variability http://www.dailymail.co.uk/health/article-1082293/The-XYY- Factor-How-rare-chromosome-disorder-brought-son-world- pain.html

Sex Chromosome Abnormalities: XXY, Klinefelter Syndrome

 Incidence 1:1000  Variable phenotype  Most common lack of secondary sex characteristics  Early developmental delay, problems with psychosocial adjustment  Verbal IQ lower than performance  Shy, immature, reserved, Smith’s Recognizable Patterns of Human awkward Malformation, 5th ed. Sex Chromosome Abnormalities: Triple X  Incidence 1/1000  Early delays in motor, language and cognitive development  Shy, withdrawn, immature, poor coordination  Depression  Psychosis  Wide variability and ascertainment bias 187 Main Street 187 Main Street Standard Cytogenetic Techniques

 Karyotype (G-bands) . Evaluation of entire genome . Resolution typically limited to 3-5 Mb

 FISH (Fluorescence in situ hybridization) . High resolution…usually ~100 kb or less . Requires a clinically directed search . Search is very specific

DiGeorge or Velocardiofacial Syndrome

Facial Features (most) .prominent nose w/ squared nasal root, small eyes, small ears w/ abnl folding

Abnormal Palate (~70%) .overt/submucous cleft

Cong. Heart Dis. (~75%) .conotruncal malformations

Learning (70-90%) http://www.sahha.gov.mt/ Hypocalcemia (40-50%) pages.aspx?page=439 Immune Deficiency .Infections http://www.medscape.co m/viewarticle/430898_4 Psychiatric Disorders

A Cytogenetically Visible Deletion is Seen in 25% of Patients With DiGeorge Syndrome.

22 del(22) FISH Detects a DiGeorge Syndrome Deletion

DiGeorge Critical TUPLE1 Region (HIRA)

CONTROL

22

. The red TUPLE1 probe which maps to the DiGeorge critical region does not hybridize to the deleted chromosome 22 22q Deletion Syndrome Includes velo-cardio- facial syndrome, Shprintzen syndrome, DiGeorge syndrome Variable dysmorphic features, cleft palate, conotruncal heart defects, hypocalcemia, learning disabilities, mild MR, psychiatric disorders 22q Deletion Syndrome – Behavioral Phenotype

 Early developmental delay and language impairment  Strong concrete skills and poor executive functioning  IQ scores decrease  Learning disabilities in math and reading comprehension – VIQ>PIQ 22q Deletion Syndrome – Behavioral Phenotype

 Psychiatric problems  ADD +/- hyperactivitiy  20% develop psychosis as adults  Lachman et a;/ 1996: COMT (breaks down dopamine) polymorphism low enzyme activity. Hemizygotes for low- activity allele have severe rapid- cycling bipolar disorder  Rx: Preventing secretion of dopamine or counteracting action Prader-Willi Syndrome

 Early hypotonia  Short stature  Small hands and feet  Hypogonadism  Intellectual disability  Hyperphagia Prader-Willi Syndrome

 In later childhood, onset of excessive appetite and obesity Prader-Willi Syndrome

 Incidence 1/15,000  Approximately 70% of cases have a cytogenetic deletion involving proximal chromosome 15 inherited from the father

Prader-Willi Syndrome: Development and Behavior

 Most have mild intellectual disability  Most learn to read and to do simple math  Temper tantrums, stubbornness, controlling/manipulative, obsessive- compulsive, food hoarding, skin and rectal picking  Autism spectrum disorder in rare cases  True psychosis in 5-10% of individuals Angelman Syndrome

 Incidence 1 in 12,000- 20,000  Approximately 70% of patients have a deletion of the same chromosome region (15q11-13) but on the chromosome 15 inherited from the mother Angelman Syndrome

 Microcephaly  Short stature  Seizures  Frequent unprovoked laughter  Severe intellectual disability Approximately 3-5% of patients with Angelman syndrome have two chromosome 15s inherited from the father (paternal UPD) Angelman Syndrome – Behavioral Phenotype

 Cognitive abilities severely to profoundly impaired  Receptive language skills higher than expressive  Attention deficit and hyperactivity  Sleep abnormalities  Aggressive behavior often attention-seeking Williams Syndrome

 Deletion 7q11.23  Elastin gene (ELN)  LIM-kinase 1 gene  Distinctive facial features  Hypercalcemia  Supravalvular aortic stenosis  Pulmonary artery stenosis Williams Syndrome

 Behavioral and developmental phenotype Very friendly, ADD, anxiety Low average to severe intellectual disability, most with mild ID

Williams Syndrome

 Behavioral and developmental phenotype Musical ability Smith-Magenis Syndrome

 17p11.2 deletion  short stature  ID, behavior abnormalities  hearing loss  synophrys  brachydactyly  heart defects http://www.gfmer.ch/genetic_diseases_v2/gendis_detail_list.ph p?cat3=931

Clinical Features in Smith- Magenis Syndrome Craniofacial Flat midface Brachycephaly Broad and square face Heavy brows with lateral extension Broad nasal bridge Full nasal tip Broad mouth with full lips Tented upper lip Malformed ears

Clinical Features in Smith- Magenis Syndrome

 Limbs Short fingers Broad hands  Hoarse voice  Congenital Heart Defects  Eye Abnormalities  Intellectual disability  Seizures

Diagnosis of Smith-Magenis Syndrome

 Clinical suspicion  Chromosome studies  Confirm with FISH analysis

Developmental/Behavioral Phenotype  Infantile hypotonia  Hyperactivity  Self-injurious behavior – onychotillomania and polyembolokoilamania  Autistic-type behavior  Self-hugging  Speech delay  Sleep disorder – hypersomnolence and lethargy in infancy, frequent nocturnal awakenings and fragmented sleep in childhood The Chromosome Microarray Technology Also Detects Copy Number Changes

 Arrayed DNA probes provide a locus-by-locus measurement of DNA copy number variation at many loci simultaneously

 Enables us to: • Survey the entire genome (like karyotyping) • Very high resolution (like FISH)

Case History

 Two year old male referred by military medical center for: “developmental delay”  Born at 36 weeks to G2P1 18yo mother  Pregnancy complicated by preterm labor  Mother reported decreased fetal movement compared to her first pregnancy  Meconium aspiration Case History

 Neurology consult at 8 months of age for developmental delay: “central hypotonia”  Normal brain MRI at 9 months  Walked at 24 months, limited speech  Surgery for ear tubes  Right sided hearing loss  No other significant illnesses, no loss of skills or regression with illness Findings  Child with global delay, mild ataxia “clumsiness”, some early features of autistic spectrum disorder with limited social interaction and speech, hypotonia  Non dysmorphic  Growth parameters Height – 25th Weight – 10th Head Circumference – 50th  Normal metabolic labs, karyotype, fragile X  Microarray: 46, XY, dup(15)(q11.2q13)

15q duplication  Duplication of PWACR  Phenotype depends on parental origin of duplication Most paternally derived duplications result in normal outcome Maternally derived duplications result in clinical phenotype Estimated prevalence in patients evaluated for autism (with normal Fragile X studies): 1/200- 1/600 15q duplication

 Clinical Features Autistic spectrum disorder Communication disorder Developmental delay Hypotonia Ataxia Seizures Mild to no dysmorphic features Macrocephaly, joint laxity

The American Journal of Human Genetics 90, 879–887, May 4, 2012 Shank genes (1,2 and 3) encode proteins that are involved in the formation and function of neuronal synapsis. All three have now been implicated in ASD.

BREAST CANCER Research and Individualized Therapy Gene Expression Next Generation Sequencing

Sanger vs. whole-exome sequencing: Technical considerations

• Sanger – 100-800+ bp – Targeted mutation analysis – Complete coverage – “Gold standard”

• WES – 30 Mb in exome (3 billion in entire genome) – Mutation fishing in many targets – Interpretation difficulties – Not considered reliable enough to use without confirmation

Illumina.com Patient NCG_00183: muscular dystrophy Conclusions Whole-exome sequencing identified the underlying genetic defect in 25% of consecutive patients referred for evaluation of a possible genetic condition. (Funded by the National Human Genome Research Institute.)

North Carolina Newborn Exome Sequencing as Universal Screening (NC NEXUS)

UNC-CH SOM one of 4 grantees in U.S. jointly funded by NHGRI and NICHD

INCIDENTAL FINDINGS

 Testing can identify things that are not related to the original intent of testing (“incidental findings”)  With next gen sequencing these can include mutations in genes such as those for breast or colon cancer, cardiac arrhythmias, intellectual disability, etc…..  What should be reported back to patients/families? Types of Genetic Testing

 Diagnostic  Predictive  Susceptibility Genetic Testing: Ethical Issues

 Genetic testing is different Implications for other family members Genetic testing of minors Privacy and discrimination issues Privacy and Discrimination

 GINA: Genetic Information Non- Discrimination Act  Passed and signed into law in 2008  Will take effect in 2009  To prevent discrimination in health insurance and employment based on  May 21, 2008: Signed into law genetic information  Health insurance to take effect by May 2009 and employers November 2009

Federal Legislation GINA . What it does not include

. Members of the military

. Life insurance, disability insurance, long- term care insurance

Patient Protection and Affordable Care Act

• Signed into law by President Obama on March 23, 2010 • Prohibits insurance companies from denying coverage of children under the age of 19 based on pre-existing conditions. Effective now. • Prohibiting insurance companies from rescinding coverage. Effective now. • Providing free preventive care (all new plans must cover mammograms, colonoscopies, etc.) Effective now. • Providing access to insurance for uninsured Americans with pre-existing conditions. Will provide new coverage options to individuals who have been uninsured for at least six months because of a pre-existing condition. States have the option of running this new program in their state. If a state chooses not to do so, a plan will be established by the Department of Health and Human Services in that state. Effective now. • Prohibiting discrimination due to pre-existing conditions or gender. The law implements strong reforms that prohibit insurance companies from refusing to sell coverage or renew policies because of an individual’s pre-existing conditions. Also, in the individual and small group market, the law eliminates the ability of insurance companies to charge higher rates due to gender or health status. Effective January 1, 2014.