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

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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

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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

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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?

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What is Autism?

• PDD-NOS?
• Asperger’s Syndrome?
• Autism Spectrum Disorder?
• Rett Syndrome?
• Childhood disintegrative

disorder?

• Autistic disorder?

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The faces of ASD

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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

• bjects, 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

2016-04-25 3 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)

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Why did this happen?

• A diagnosis of autism is a behavioral diagnosis via
• bservation
• indicates nothing about the underlying cause

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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

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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

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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

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Environment Genetics

These known causes can explain ~30% of autism spectrum disorder

In-utero exposure

Genetics and Environment are NOT Separate Entities

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Advanced Paternal Age

?

?

? ?

WHY did this happen?

These known causes account for ~30% of all autism

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Prenatal Exposure

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Prenatal Exposure

Medications:

• Example: Valproic acid

(anti-convulsant)

• Dysmorphic facies
• Congenital heart defects
• Spina Bifida
• Intellectual disability

and/or autism

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Prenatal Exposures

Maternal infection:

• Example: Rubella (N.M. Gregg,

1941)

• 1st and early 2nd trimester
• Clinical features:
• Early: miscarriage, Sensorineural

hearing loss, Intellectual disability, cataracts, congenital heart disease, “blueberry muffin”

• Late: Intellectual disability,

microcephaly, autism

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2016-04-25 7 How Genetic is ASD?- 4:1 Gender Difference

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How Genetic is ASD?- Concordance studies

Identical Twins ~80% concordance Fraternal Twins ~30% concordance Siblings ~20% concordance

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How Genetic is ASD? - Compared to other Conditions

Diabetes Alzheimer’s Disease Cancer Autism Cystic Fibrosis

Not Genetic Completely Genetic

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How Genetic is ASD?- Ultimately, this answers differs with each child

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How Genetic is ASD? Factors that influence likelihood

Low functioning Complex Syndromic Dysmorphic Regressive Familial High Functioning Primary Non-syndromic Non-dysmorphic Static Simplex

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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

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The Role of the Geneticist and Genetic Counselor

WHAT WE DO:

• Try to identify an

underlying cause for ASD

• Provide appropriate

genetic counseling to family

• Provide support to family

WHAT WE DO NOT DO:

• Make the diagnosis of ASD
• Provide treatment

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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?

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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

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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.”

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Fragile X syndrome

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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

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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

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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

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http://www.fragilexfiles.com/2013/01/fragile-x-writers-series-when-all-3-of.html

"I'm a mom of 3 children with Fragile X Syndrome.“ -Rachael Gibson, Blogger

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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

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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.”

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2016-04-25 13 Example: 16p11.2 microdeletion syndrome

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16p11.2 microdeletion syndrome

• delay in starting to speak and in language

development

• Some developmental delay or learning

difficulty.

• An increased susceptibility to autism

spectrum disorder (~1/5?)

• Very minor unusual facial or physical

features

• Low muscle tone in babies
• Tendency to be overweight
• Increased risk for seizure disorder
• Some have no symptoms at all

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http://www.rarechromo.org/information/Chromosome%2016/16p11.2%20microdeletions%20FTNW.pdf

Rett Syndrome

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Classic Rett Syndrome

• Only females affected
• MECP2 gene mutation
• Developmental regression typically 12-24

months old

• Acquired microcephaly
• Seizures in 90%
• Stereotypical Hand wringing-loss of

purposeful hand movements

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Rett Syndrome

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Atypical Rett Syndrome

• Rett Syndrome possibly exists on a larger

spectrum than previously thought

• more milder cases being reported with

increase in genetic testing:

• Later onset
• incomplete symptoms and prolonged course
• Preserved speech

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PTEN-ASD Syndrome

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PTEN-ASD Syndrome

• ASD and Macrocephaly- Head Circumference

>2 SD above the curve

• Prevalence unknown but considered rare
• Risk for cancer in later life?
• Potential cancer risk for parents if inherited

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Metabolic Work-up

• Inability to metabolize certain

proteins or amino acids

• Much is done on State Newborn

Screen

• it is important for physicians to know

where and when a child was born and update metabolic testing as needed

• Metabolic work-up should be

considered in any child born outside USA with unexplained neurologic symptoms

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Gene Panel Testing

Testing for multiple other Single gene disorders (~5%):

• Tuberous sclerosis complex
• Mitochondrial disorders (associated w elevated plasma

lactate; very rare)

• NF1
• CHARGE Syndrome
• Many others: Cornelia de Lange, Smith-Lemli-Opitz,

Sotos Syndrome, etc.

• How many genes is enough?

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Whole Exome Sequencing

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Pros:

• currently one of the most comprehensive

genetic tests available

• able to analyze approximately 95% of the exome
• Highest likelihood of detection

Cons:

• Possibility of detecting other genetic syndromes
• r susceptibility gene unrelated to the ASD in

child or parents

• Many possibilities for variants of uncertain

clinical significance

Whole Exome Sequencing

• Hundreds of genes associated with autism have

been discovered with WES

• Mutations in these genes render the individual

susceptible to ASD

• All together all genetic tests still only explain ~25% of

autism

• No one cause explains more than 1-3% of autism
• May explain the “spectrum” to some extent

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Whole Exome Sequencing

Most genes are of three types:

• Involved in synaptic formation & function
• Genes that regulatory gene expression
• Involved in chromatin formation and packing
• Most mutations are de novo and may be

associated with advanced parental age.

(M. State et al., October 2014)

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Most is Essential/Idiopathic Autism

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Why “WHY?” Matters

• Identifying genes helps to understand the

underlying cause for autism and how brains of children with autism may function differently than others

• This can ultimately lead to new interventions,

development of drugs, educational strategies and devices and/or other biochemical tests for autism

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QUESTIONS?