Genetic Aspects of Autism

1. Genetic Aspects of Autism Janice Palumbos, MS, CGC Genetic Counselor University of Utah

2. Autism • Autism is a complex, behaviorally defined, static disorder of the brain • Autism is not a disease but a syndrome with multiple nongenetic and genetic causes

3. Autism • Hetereogenous etiology • Identifiable syndromes account for very small minority • 90 to 95% have no identifiable cause • About 75% have a lifelong disability requiring intense parental, school and societal support

4. Coexisting conditions with Autism • 50 to 70% of children with autism have MR by nonverbal IQ testing • Seizures develop in 25% of children with autism • Dysmorphic features in 25% • Few have identifiable structural brain malformation and microcephaly in 5% - poorer prognosis • Association with Macrocephaly

5. Importance of identifying a syndrome Different implications for: • Etiology • Prognosis/natural history/what to expect • Medical management/Surveillance • Recurrence risks • Availability of prenatal diagnosis

6. Syndromes associated with autism • Fragile X • Rett syndrome • Tuberous Sclerosis • Sotos syndrome • PTEN • NF1 – true association or chance? • RTS- larger deletions associated with autistic spectrum • Mitochondrial? • Chromosome abnormalities 15q duplication Down syndrome

7. Fragile X • Most common form of inherited MR • Caused by increased CGG repeats of FMR1 gene on X chromosome • Males affected more severely • Males have moderate MR, characteristic face, large ears, large testicles, joint mobility • Girls may have mild MR

8. Behavior in Fragile X Hyperactivity, impulsivity Social anxiety Poor eye contact, Gaze avoidance Self-injury, usually hand-biting in response to anxiety or excitement Delayed imitative and social play Stereotyped and repetitive behaviors

9. Fragile X • 1 in 1,200 males • 1 in 2,500 females • 1 in 3 with Fragile X syndrome have autism • 2% to 6% of children with autism have Fragile X

10. Rett syndrome • Neurodevelopmental disorder characterized by normal early development followed by loss of purposeful use of the hands, distinctive hand movements, slowed brain and head growth, gait abnormalities, seizures, and mental retardation. • Affects females almost exclusively. • Hypotonia is usually the first symptom. As the syndrome progresses, the child loses purposeful use of her hands and the ability to speak. Other early symptoms may include problems crawling or walking and diminished eye contact.

11. Rett syndrome • Caused by change in MECP2 gene on X chromosome - insufficient amounts or structurally abnormal forms of the protein are formed – Mutation found in about 80% • X-linked dominant • 1% of children with autism have MECP2 gene change.

12. Tuberous Sclerosis Complex (TSC) • Autosomal dominant, neurocutaneous condition • 2 different genes- TSC1 (9q34) and TSC2 (16p13.3) – tumor suppressor genes • Classic triad: Mental retardation, Seizures, Skin findings • Multisystem disorder – eyes, kidney, brain, skin

13. TSC: Neurodevelopmental aspects • Cognition • 55% have IQ>70; 12 points lower than sib • 30% have IQ<21 • Behavior problems- even with normal IQ • Aggression, overactivity, impulsivity, anxiety, depression

14. Skin findings in Tuberous Sclerosis Ash Leaf spot Adenoma Sebaceaum Shagreen Patch

15. Brain findings in TSC • Cortical Tubers • Subependymal nodule • Subependymal giant cell astrocytoma • Retinal nodular fibromas

16. Tuberous Sclerosis • 25% of intellectually disabled individuals with tuberous sclerosis (TSC) have autism • 1.1% to 1.3% of individuals with autism have TSC • Relationship of seizures, brain tubers and autism not well understood

17. Sotos syndrome • Overgrowth • Macrocephaly • Broad forehead and pointed chin • Advanced bone age • Developmental delay • Risk for tumors/CA • Autism • NSD1 gene – mutations and microdeletions – 5q35

18. Neurofibromatosis, type 1 • Autosomal Dominant • Neurocutaneous syndrome • Very common -1/3000 • Gene located on chromosome 17 – tumor suppressor gene

19. Skin Findings in NF 6 or more cafe-au-lait spots on the skin Presence of benign tumors (neurofibromas) on the skin Larger areas on the skin that look swollen (plexiform neurofibromas) Freckling under the arms or in the groin area

20. Lisch nodules on the iris of the eye Tumor/ enlargement of the optic nerve Eye findings in NF-1

21. Bone findings in NF-1 • Tibial bowing • Pseudoarthrosis or bowing of other long bones • Scoliosis • Sphenoid wing dysplasia

22. Neurofibromatosis, type 1 • 50% Learning Disabilities • About 1/3 have significant medical complication • Increased incidence of autism

23. PTEN Hamartoma Tumor Syndrome Autosomal Dominant PTEN gene 10.q23.31 Macrocephaly Hamartomas – lipomas, intestinal polyps, Penile macules (dark spots) Cancer susceptibility syndrome (breast, thyroid, endometrium) Tumor suppressor gene –also called Cowden syndrome At least 4 studies have identified PTEN mutations in children with autism and macrocephaly

24. “Screening of PTEN mutations is warranted in patients with autism and pronounced macrocephaly, even in the absence of other features of PTEN-related tumor syndromes.”

25. PTEN knockout mice • SHOW AUTISTIC BEHAVIOR! • Showed no interest in strange mice. • Were equally interested in another mouse and an inanimate object. • Ignored new nesting material. • (Females) were unable to care for their young with many dying. • Became very stressed in open spaces. • Became very stressed when gently picked up by humans. • Were much more stressed by sudden noises.

26. 3 copies of small region of chromosome 15 • As many as 3% of individuals with autism have a maternally inherited duplication in the Prader-Willi/Angelman syndrome region of 15q11 – q13. • Isodicentric chr 15 duplication- morecommon, more severe • Interstitial Chr 15 duplication • 50% have autism

27. Chromosome 15 duplication • Poor Muscle Tone –early central hypotonia • Cognitive disabilities/learning disabilities • Autism spectrum disorders • Seizure Disorders • Speech/Language Delay • Sensory Processing Disorders • Attention Deficit Disorders (ADD/ADHD) • Anxiety Disorders • Small size for age • Minor unusual facial and physical features • Occasional birth defects – oralfacial cleft, kidney, heart

28. Other Chromosome abnormalities are associated with autism • Down syndrome • Duplication of Williams syndrome gene 7q11.23 - Severe expressive language disorder, dd • 2q deletion, 18q deletion, 22q13.3 deletion, others including apparently balanced rearrangements reported in literature with autism • 3-5% of individuals with autism? Estimates vary

29. Chromosome 16 • About 1% of people with autism have a 500-kilobase region of the short arm of the chromosome 16 either missing or duplicated • 16p del or dup has hundredfold risk of developing autism in contrast to those without it • 16p11.2 • 25 genes • Detectable by cgh microarray • Reported January 2008

30. When to refer a child with autism to Genetics? Autism with additional finding(s): • Birth Defects • Multiple minor anomalies • Facial features different than family background • Microcephaly or macrocephaly • Skin findings: white spots, brown spots, signs of neurocutaneous syndrome • Positive family history • Seizures • Mental retardation • Any child with autism if family requests genetic counseling

31. Evaluation Strategy • Family History • Clinical examination Height, weight, OFC Dysmorphology exam Examination of skin • Testing depends on above but may include chromosomes, Fragile X, cgh microarray, testing for single gene disorders, metabolic testing • Genetic counseling

32. Idiopathic Autism • Male to Female ratio of 3:1 • Skewed ratio unexplained • X-linked conditions may contribute but not explain • Male to male transmission excludes X-linked conditions for most cases

33. Increased risk of autism recurrence for siblings • Population rate of autism is 16/10,000 or almost 0.2% • Overall Risk of autism to siblings is about 4.5% • Ratio of sibling recurrence risk to general population risk, lR is 22.5 (increase of risk 22.5 times) • Higher than the prevalence rate in the general population but much lower than in single-gene diseases • Heritability estimate = 90%

34. The recurrence risk issue is more complex…Milder phenotype risks • Although empiric risk is 4 to 4.5% for autism is siblings, there may be additional risk of 4-5% for milder symptoms including language and social problem.

35. The recurrence risk issue is more complex… Brothers and Sisters • Recurrence risk is higher if affected child is female. (Utah-UCLA study 14.5% recurrence risk if affected child was female vs. 7.7% for male. ) • Brothers have higher risk than sisters. • Idiopathic autism with no other findings: Brothers of a proband have 7% risk of autism and additional 7% risk for milder symptoms • Sisters of proband with essential autism have a 1% risk for autism; unknown risk for milder autistic spectrum disorder.

36. Evidence that “Idiopathic" autism is a heritable disorder • Monozygotic twins – 60% concordance for autism to 90% concordance for autism spectrum/Communication and Language disorders • Dizygotic twins – share 50% of nuclear genes- range from 0 to 10% concordance

37. Appreciation for the complexity • Autism overlaps with other brain disorders • Autism is not a single disorder but probably many disorders • Many genes may be involved • 3-10 (Pickles et al.) • 20 or more (Risch et al.) • Methylation, imprinting, and alternate splicing of proteins may also be involved (e.g. Chr 15q11-13) • Environmental factors may also vary • At the mildest end of the spectrum, autism traits may represent variation of common normal traits (e.g. ability to focus)

38. Summary of Genetics of Autism • Currently, diagnosable medical conditions, cytogenetic abnormalities, and single-gene defects together account for <10% of cases • Value of Genetics evaluation • Idiopathic autism has a genetic component • Parents who have one child with idiopathic autism have a 4.5% to have another child with autism – Brothers have higher risk; Risk is higher if affected child is a female.