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Genetics of Autism Spectrum Disorder PowerPoint Presentation

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Description : Check out this medical presentation on Cowden Syndrome, which is titled "Genetics of Autism Spectrum Disorder", to know about your local genetics centre and/or order genetic testing appropriately for autism spectrum disorders (ASD), understand the features that distinguish non-syndromic from syndromic ASD (ASD plus), and find high quality genomics educational resources appropriate for primary care.

Tags : Cowden Syndrome, Genetics, Autism Spectrum Disorder, genetics centre, autism spectrum disorders, ASD

Published on : May 13, 2021 | Views : 1263 | Downloads : 8

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Slide 1-

Genetics of Autism Spectrum Disorder Developed by Dr. Judith Allanson, Dr. June Carroll, Ms. Shawna Morrison and Ms. Safa Yusuf
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Disclaimer This presentation is for educational purposes only and should not be used as a substitute for clinical judgement. GEC-KO aims to aid the practicing clinician by providing informed opinions regarding genetic services that have been developed in a rigorous and evidence-based manner. Physicians must use their own clinical judgement in addition to published articles and the information presented herein. GEC-KO assumes no responsibility or liability resulting from the use of information contained herein.
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Objectives Following this session the learner will be able to: Refer to their local genetics centre and/or order genetic testing appropriately for autism spectrum disorders (ASD) Understand the features that distinguish non-syndromic from syndromic ASD (ASD plus) Find high quality genomics educational resources appropriate for primary care
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What is autism spectrum disorder? ASD is a complex group of neurodevelopmental disorders childhood disintegrative disorder autistic disorder pervasive developmental disorder-not otherwise specified Asperger syndrome
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What is autism spectrum disorder? ASD is a complex group of neurodevelopmental disorders Core features are:
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What is autism spectrum disorder? ASD is a complex group of neurodevelopmental disorders Core features are: communication and social interaction deficits, repetitive behaviours and/or restricted interests. 1 in 68 children are affected Males affected at a ratio of about 4:1
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What is autism spectrum disorder? ASD is a complex group of neurodevelopmental disorders Core features are: communication and social interaction deficits, repetitive behaviours and/or restricted interests. 1 in 68 children are affected Males affected at a ratio of about 4:1 Diagnosis is made with the Diagnostic and Statistical Manual of Mental Disorders [DSM] criteria Autism Diagnostic Observation Schedule-2 [ADOS] Modified Checklist for Autism in Toddlers-Revised (M-CHAT-R™)
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Is autism spectrum disorder genetic? Genetically influenced disorder, caused by factors including: ~15-40% of individuals with ASD will have an identifiable genetic cause factors that affect gene expression and activity Genetic Epigenetic Non-genetic environmental exposures 60%, no known genetic etiology
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Genetic diagnosis in autism spectrum disorder A genetic etiology can be identified in up to 40% of individuals with ASD Isolated ASD plus Clinical presentation
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Genetic diagnosis in autism spectrum disorder A genetic etiology can be identified in up to 40% of individuals with ASD Isolated ASD plus Chromosomal microarray (10%) Gene/Syndrome specific (<14%) Fragile X syndrome (1–5%) Rett syndrome (MeCP2) (4% of females) Cowden syndrome (PTEN) (5%) Karyotype (3%) Other (10%) Clinical presentation Technology
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A genetic etiology can be identified in up to 40% of individuals with ASD. A genetic diagnosis can: 1. Guide management Cowden syndrome, PTEN High risk for benign and malignant tumors of the thyroid, breast, and endometrium and intestinal polyposis ASD Macrocephaly (>3SD) Five benefits of genetic diagnosis in autism spectrum disorder
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Genetic counselling can provide: Information psychosocial support both immediate and in the long term guidance and help to prepare for the future facilitate family communication aid in decision making Even when a diagnosis cannot be made Support 2. Benefit patients and their families Three facts about genetic testing in autism spectrum disorder A genetic etiology can be identified in up to 40% of individuals with ASD. A genetic diagnosis can: Diagnosis 1. Guide management
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A genetic etiology can be identified in up to 40% of individuals with ASD. A genetic diagnosis can: 1. Guide management 2. Benefit patients and their families Unknown 10-19% (empirical risk) ~32% when 2 children affected de novo Genetic Etiology Recurrence risk estimate <1% Autosomal recessive X-linked 50% different presentation in males and females Autosomal dominant 25% 50% Five benefits of genetic diagnosis in autism spectrum disorder Recurrence risk counselling Diagnosis Support
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A genetic etiology can be identified in up to 40% of individuals with ASD. A genetic diagnosis can: 1. Guide management 2. Benefit patients and their families 3. Allow for familial testing At-risk family members may need screening Cowden syndrome is autosomal dominant 50% risk to parents and sibs Prenatal diagnosis Five benefits of genetic diagnosis in autism spectrum disorder
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A genetic etiology can be identified in up to 40% of individuals with ASD. A genetic diagnosis can: 1. Guide management 2. Benefit patients and their families 3. Allow for familial testing Rett syndrome (MeCP2) Progressive neurodevelopmental disorder Normal development until 6-18 months Developmental stagnation and then regression 4. Allow families and providers to better understand the natural history and prognosis of a condition Five benefits of genetic diagnosis in autism spectrum disorder
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A genetic etiology can be identified in up to 40% of individuals with ASD. A genetic diagnosis can: 1. Guide management 2. Benefit patients and their families 3. Allow for familial testing 4. Allow families and providers to better understand the natural history and prognosis of a condition 5. Allow for access to specialized support Five benefits of genetic diagnosis in autism spectrum disorder
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How do I know if my patient’s autism spectrum disorder is genetic? ASD diagnosis is confirmed Isolated ASD? ASD plus?
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How do I know if my patient’s autism spectrum disorder is genetic? Order first tier genetic testing Offer referral to genetics (1-2 year wait) ASD diagnosis is confirmed Isolated ASD ASD plus
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First tier genetic testing for autism spectrum disorder 1. Chromosomal microarray Chromosomal microarray for ASD may be ordered by primary care providers. To find out more, please call your local genetics lab. If you are unable to order a chromosomal microarray, you may be referred to a pediatrician or developmental pediatrician. 2. Fragile X syndrome testing
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What is chromosomal microarray? Genomic technology to assess for small extra (micro-duplication) or missing (micro-deletion) pieces of genetic information These gains and losses are called copy number variants (CNVs) Higher resolution genetic test than karyotype Yield for individuals with ASD is~7-14% Finucane 2016 Curr Genet Med Rep
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Chromosomal microarray results CNV – Copy Number Variant Negative Cannot completely rule out a CNV in all areas of the genome Cannot exclude a syndrome caused by a mutation within a single gene Cannot detect balanced chromosome differences No significant CNVs detected
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Chromosomal microarray results Negative No significant CNVs detected Screening/surveillance/treatment Recurrence risk counselling Support organization Familial testing Clinical trial Positive Pathogenic or likely pathogenic CNV detected Diagnostic 16p11.2 CNVs Deletion or duplication ~1% of individuals with ASD CNV – Copy Number Variant Offer referral to Genetics
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Chromosomal microarray results Variant of Uncertain Significance (VUS) A CNV that has not yet been classified as benign or pathogenic Negative No significant CNVs detected Positive Pathogenic or likely pathogenic CNV detected CNV – Copy Number Variant Test the parents (trio) Offer referral to Genetics
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Chromosomal microarray results Variant of Uncertain Significance (VUS) A CNV that has not yet been classified as benign or pathogenic Negative No significant CNVs detected Positive Pathogenic or likely pathogenic CNV detected CNV – Copy Number Variant Finding in the child is pathogenic, but parent displays reduced penetrance (not everyone with the CNV will have symptoms), variable expressivity (individuals with this CNV have varied presentation) A second predisposing factor is needed to cause problems Both parents have normal array results Finding in child is new, de novo Likely pathogenic One parent has same array result as child Finding in the child is normal familial variant Not pathogenic Test the parents (trio)
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Chromosomal microarray results Variant of Uncertain Significance (VUS) A CNV that has not yet been classified as benign or pathogenic Negative No significant CNVs detected Positive Pathogenic or likely pathogenic CNV detected CNV – Copy Number Variant Incidental finding A genetic variant that is unrelated to the primary indication for testing Offer referral to Genetics Predisposition to adult onset disorder e.g. Lynch syndrome Carrier status e.g. cystic fibrosis
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Fragile X syndrome Most common inherited form of intellectual disability 1 in 4,000 boys and 1 in 6,000 girls Large head, long face, prominent forehead and chin, protruding ears Behavior differences e.g. hyperactivity, hand flapping, tactile defensiveness Global DD & intellectual disability 25% will have ASD Of children with ASD, 1-5% will have a fragile X syndrome diagnosis
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Fragile X syndrome Caused by a triplet repeat expansion in the FMR1 gene Associated with abnormal methylation (shutting off the gene) CGG CGG CGG CGG CGG CGG CGG CGG CGG CGG CGG 200+ repeats is a full expansion Pre-mutation carriers (55-200 CGG repeats) are at risk for fragile X- associated tremor/ataxia syndrome (FXTAS) [men>women] and women are at risk for premature ovarian failure (~20%)
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How do I know if my patient’s autism spectrum disorder is genetic? Offer referral to genetics Variant of Uncertain Significance (VUS) Positive Incidental finding Negative End of investigations Reassess at regular intervals If new medical or developmental concerns present, consider referral to Genetics Refer to specialized interventions as needed Order first tier genetic testing ASD diagnosis is confirmed Isolated ASD? ASD plus? For ASD plus
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Colin is 6. He is a tall boy with a large head. He has been diagnosed with autism by ADOS. You are referring him to Genetics, but the wait is likely to be 2 years. In the meantime you want to organize first tier Genetic testing. What test should you order? You order chromosome analysis You order Fragile X gene testing You order a microarray You order chromosome analysis and Fragile X gene testing You order Fragile X gene testing and a microarray
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Colin is 6. He is a tall boy with a large head. He has been diagnosed with autism by ADOS. You are referring him to Genetics, but the wait is likely to be 2 years. In the meantime you want to organize first tier Genetic testing. What test should you order? You order chromosome analysis You order Fragile X gene testing You order a microarray You order chromosome analysis and Fragile X gene testing You order Fragile X gene testing and a microarray
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Parents of a child with autism may find which of the following aspects of genetic testing valuable? Confirmation of the diagnosis of autism in their child Knowledge of the cause of autism in their child Understanding of recurrence risk in a future pregnancy All of the above A and B B and C
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Parents of a child with autism may find which of the following aspects of genetic testing valuable? Confirmation of the diagnosis of autism in their child Knowledge of the cause of autism in their child Understanding of recurrence risk in a future pregnancy All of the above A and B B and C
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Where do I find more information? www.geneticseducation.ca Check with your local genetics clinic about how testing may be organized