2016-04-25 What does DNA have to do with it? The basics you should - PDF document

2016-04-25 What does DNA have to do with it? The basics you should know about genetics and Autism Spectrum Disorder Katie Gallagher, MS, CGC Genetic Counselor Boston Children’s Health Physicians Valhalla, NY 4/29/16 1 Goals • Review the known causes of Autism Spectrum Disorder • Discuss the growing availability of genetic testing for ASD • Review the role of geneticists and genetic testing in the management of children with ASD • Discuss the benefits and limitations of genetic testing for ASD for individuals, families, physicians and educators 2 Questions to geneticist from families • What is autism? • Why did this happen? • Could this happen again? • What will happen in the future? • What is the treatment? 3 1

2016-04-25 What is Autism? • PDD-NOS? • Asperger’s Syndrome? • Autism Spectrum Disorder? • Rett Syndrome? • Childhood disintegrative disorder? • Autistic disorder? 4 The faces of ASD 5 What is Autism DSM 5 criteria- May 2013 A. Persistent deficits in social communication and social interaction across multiple contexts, as manifested by the following, currently or by history: Deficits in social-emotional reciprocity…Deficits in nonverbal communicative behaviors used for social interaction… Deficits in developing, maintaining, and understanding relationships… B. Restricted, repetitive patterns of behavior, interests, or activities , as manifested by at least two of the following, currently or by history: Stereotyped or repetitive motor movements, use of objects, or speech…Insistence on sameness…Highly restricted, fixated interests that are abnormal in intensity or focus….Hyper - or hyporeactivity to sensory input C. Symptoms must be present in the early developmental period (but may not become fully manifest until social demands exceed limited capacities, or may be masked by learned strategies in later life). D. Symptoms cause clinically significant impairment in social, occupational, or other important areas of current functioning. E. These disturbances are not better explained by intellectual disability (intellectual developmental disorder) or global developmental delay. Intellectual disability and autism spectrum disorder frequently co-occur; to make comorbid diagnoses of autism spectrum disorder and intellectual disability, social communication should be below that expected for general developmental level 6 2

2016-04-25 How is the diagnosis made? • Best made by a multidisciplinary team that includes: • Developmental-Behavioral Pediatrician • Psychologist/ Psychiatrists • Speech & Language Therapist • Neurologist • Others • Evaluation should include: • History: Attainment of developmental & social landmarks (pointing) • Observation of play & social interactions • Physical exam: Looking for clues to a syndromic diagnosis • Performance of “gold standard” tests, such as the Autism Diagnostic Observation Schedule (ADOS) 7 Why did this happen? • A diagnosis of autism is a behavioral diagnosis via observation • indicates nothing about the underlying cause 8 Why “WHY?” Matters • Answers • Recurrence risk • Support groups • Anticipatory guidance • Medical management and screening • Therapy qualification • insurance coverage • Treatment • Assist educators and caregivers in understanding the most likely areas of need 9 3

2016-04-25 The Limitations of Knowing Why • The diagnosis/interventions for autism are typically applied the same regardless of the cause • Little help with prognosis- we do not yet know of biological differences predicting “where on the spectrum” someone may be and how that may change throughout life • Some children with “genetic susceptibility” to autism will never develop autism • Therefore, genetic testing for ASD is not designed to diagnose it is designed to understand “why” for those already diagnosed 10 11 Is there really an epidemic of ASD? • Possible reasons for increased prevalence: • More awareness by professionals • Detection of milder cases (changes in definition) • Environmental causes on the increase? • Unknown: there really is an epidemic 12 4

2016-04-25 13 Genetics and Environment are NOT Separate Entities ? ? Genetics In-utero exposure ? Advanced ? Environment Paternal Age These known causes can explain ~30% of autism spectrum disorder 14 WHY did this happen? These known causes account for ~30% of all autism 15 5

2016-04-25 Prenatal Exposure 16 Prenatal Exposure Medications: • Example: Valproic acid (anti-convulsant) • Dysmorphic facies • Congenital heart defects • Spina Bifida • Intellectual disability and/or autism 17 Prenatal Exposures Maternal infection: • Example: Rubella (N.M. Gregg, 1941) • 1 st and early 2 nd trimester • Clinical features: • Early: miscarriage, Sensorineural hearing loss, Intellectual disability, cataracts, congenital heart disease, “blueberry muffin” • Late: Intellectual disability, microcephaly, autism 18 6

2016-04-25 How Genetic is ASD?- 4:1 Gender Difference 19 How Genetic is ASD?- Concordance studies Identical Twins Fraternal Twins ~80% concordance ~30% concordance Siblings ~20% concordance 20 How Genetic is ASD? - Compared to other Conditions Completely Genetic Cystic Fibrosis Autism Cancer Alzheimer’s Disease Diabetes Not Genetic 21 7

2016-04-25 How Genetic is ASD?- Ultimately, this answers differs with each child 22 How Genetic is ASD? Factors that influence likelihood Low functioning Complex Syndromic Dysmorphic Regressive Familial High Functioning Primary Non-syndromic Non-dysmorphic Static Simplex 23 How Genetic is ASD? Factors that influence likelihood • Lack of family history ≠ not genetic • Family history ≠ genetic • May be genetic but not inherited (“de novo”) • May have different symptoms in each family member with the same genetic finding • Some individuals may be asymptomatic and may still pass on “autism susceptibility” to offspring 24 8

2016-04-25 The Role of the Geneticist and Genetic Counselor WHAT WE DO: WHAT WE DO NOT DO: • Try to identify an • Make the diagnosis of ASD underlying cause for ASD • Provide treatment • Provide appropriate genetic counseling to family • Provide support to family 25 Tiered Testing • Recommendations for testing in children with ASD: Tier 1: • Fragile X DNA analysis • Chromosomal microarray analysis Tier 2: • Consideration of Rett Syndrome and PTEN syndrome • Metabolic testing if clinically indicated • +/- EEG and Brain MRI (especially with regression or micro/macrocephaly) Tier 3: ASD Gene Panel Tier 4: Whole Exome Sequencing? 26 Fragile X Syndrome • “most common inherited form of ID/ASD in boys” • Approximately 20% of boys with fragile X syndrome meet diagnostic criteria for ASDs when evaluated by objective criteria. • Studies have found an incidence of abnormal fragile X studies of ~2-6% in unselected cohorts of boys with ASD 27 9

2016-04-25 ACMG recommendation The American College of Medical Genetics recommends testing for Fragile X for: “Individuals of either sex with mental retardation, developmental delay, or autism, especially if they have (a) any physical or behavioral characteristics of fragile X syndrome, (b) a family history of fragile X syndrome, or (c) male or female relatives with undiagnosed mental retardation .” 28 Fragile X syndrome 29 Fragile X Syndrome: Clinical Features • Characteristic facial appearance (prominent forehead, ears, jaw) • Connective tissue: Joint laxity & Mitral valve prolapse • Macrocephaly & tall stature in early childhood • Macro-orchidism (notable after puberty) • Intellectual disability and/or ASD 30 10

2016-04-25 31 Fragile X Syndrome: Inheritance CATEGORIES OF CGG REPEATS: • 0- 45 CGG repeats (“normal”) • 45- 54 CGG repeats (“gray zone”) • 55-200 CGG repeats (“ premutation carrier”, unaffected*) • >200 CGG repeats (“full mutation”, affected) *No ID/ASD, but POI and FRA-X T/A 32 Fragile X Syndrome: Inheritance • Inherited from mother to child • Up to 50% chance of passing on a full mutation to offspring • Male offspring typically more symptomatic than females • Carrier and prenatal testing are available • Repeat # does not predict severity 33 11

2016-04-25 "I'm a mom of 3 children with Fragile X Syndrome .“ -Rachael Gibson, Blogger 34 http://www.fragilexfiles.com/2013/01/fragile-x-writers-series-when-all-3-of.html Chromosomal Microarray Analysis (CMA) • Typically individuals have 2 copies of every gene • Analysis for microdeletions and microduplications (“copy number variants (CNVs)”)in the chromosomes • Yield of 15-20% cause of ASD • Many variants of uncertain clinical significance reported 35 ACMG Recommendation “ 1. CMA testing for CNV is recommended as a first-line test in the initial postnatal evaluation of individuals with the following: A. Multiple anomalies not specific to a well- delineated genetic syndrome. B. Apparently nonsyndromic DD/ID. C. Autism spectrum disorders.” 36 12