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Genetics of Intellectual Disability

Genetics of Intellectual Disability. Eric M. Morrow MD PhD Assistant Professor, Brown University eric_morrow@brown.edu. Overview. Define intellectual disability Outline the scope of the problem Genetic architecture Chromosomal, copy number variants X-linked Autosomal dominant/recessive

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Genetics of Intellectual Disability

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  1. Genetics of Intellectual Disability Eric M. Morrow MD PhD Assistant Professor, Brown University eric_morrow@brown.edu

  2. Overview • Define intellectual disability • Outline the scope of the problem • Genetic architecture • Chromosomal, copy number variants • X-linked • Autosomal dominant/recessive • Metabolic disorders • Mitochondrial • Neurobiology • Treatments • Ethical issues • Future research

  3. Themes • Heterogeneity, heterogeneity, heterogenetiy • Most genetic mutations that have been found in autism and related disorders have also been found in ID

  4. Intellectual disability and American History

  5. Diagnosis: DSM-IV-TR • Does anyone know what Axis is intellectual disability on?

  6. Diagnosis: DSM-IV-TR Definition: • Significant sub-average intellectual function, IQ<70 • Significant limitations in adaptive function • Onset before age 18 years of age

  7. Diagnosis continued: • Borderline IF – 70-80 IQ • Mild – 50-70 IQ • Moderate – 35-50 IQ • Severe – 20-35 IQ • Profound <20 IQ • Syndromic ID vs. Non-syndromic ID

  8. Prevalence • Children 8 years of age • 2000 Surveillance Year per 1,000 children: Intellectual Disability 12.0 Cerebral palsy 3.1 Hearing loss 1.2 Vision impairment 1.2 Autism Spectrum Disorders 6.5 • 1991, 1/63; many regions of the world prevalence is higher. Metropolitan Atlanta Developmental Disabilities Surveillance Program

  9. Costs • The average lifetime cost for an individual with intellectual disability is estimated by the CDC to be $1,014,000, or over $50 billion for a single cohort of individuals with ID born in the year 2000. Honeycutt AA, Grosse SD, Dunlap LJ, et al., eds. Economic costs of mental retardation, cerebral palsy, hearing loss, and vision impairment. Amsterdam: Elsevier; 2003. Altman BM, Barnartt SN, Hendershot GE, Larson SA, eds. Using survey data to study disability: results from the National Health Interview Survey on Disability. Research in social science and disability.; No. 3.

  10. Overlap between Autism and Intellectual Disability • Controversial subject • Approximately 50% of children with ASD diagnosis have ID (ADDM). • approximately 25-40% of individuals with ID also meet criteria for an autism diagnosis Bradley EA, Summers JA, Wood HL, Bryson SE. Comparing rates of psychiatric and behavior disorders in adolescents and young adults with severe intellectual disability with and without autism. J Autism Dev Disord. Apr 2004;34(2):151-161.

  11. Questions which guide the hypothesis about genetic architecture: • Is the condition heritable? Genes vs Environmental • What is the mode of inheritance? • Autosomal, sex-linked, dominant, recessive, complex • What is the nature of the variant? • Chromosomal, sequence or copy number variant • Is the variant(s) old or new? • Inherited vs. de novo • What is the frequency of the variant in the population? • Common (>5%) or rare (<1%) • What are the evolutionary pressures (positive or negative) on the

  12. Good News in the Post-Genome Era • The screen has already been done for you • The world is your petri dish • Airplanes • Internet • Video-conference • Couriers • New sequencing Methods • Completed genome maps

  13. Genetic Heterogeneity • Given one clinical presentation, there are a wide variety of singular and distinct genetic causes. • Non-syndromic ID fits this definition perfectly.

  14. Chromosomal Aneuploidies • Trisomy 21 (1 in 800 births) • Trisomy 18 (Edwards syndrome – 1 in 6000) • Trisomy 13 (Patau syndrome – 1 in 10,000) • Turners syndrome X0 • Klinefelters syndrome XXY • Numerous individually heterogeneous disorders, such as microscopic deletions, duplications, translocations (balanced and unbalanced).

  15. Downs syndrome • What would the pedigree look like for Downs syndrome? • Would the twin studies indicate high heritability?

  16. Classic Genomic Disorders • Cri du chat • Williams syndrome • Angelman syndrome • Prader-Willi syndrome • Smith-Magenis syndrome • DiGeorge syndrome

  17. R R VCFS-D VCFS-B VCFS-A VCFS-G DGCR6 DGCR5 GP1BB TMVCF PNUTL TBX1 PRODH2 CALS2? PIK4CA ZNF74 VCFS-C PCQAP IDD CTP DGS-I / ES-2 GSCL TSK-1 NOGOR PRODH2-p ARVCF DGCR6 SRECII SERPIND1 SNAP29 CRKL VCFS-E LZTR VCFS-F P2RXL1 SLC7A4 CTLD HIRA NLVCF WDR14 COMT T10 DGCR8 HTF9C RANBP1 KIAA1292 ZNF TRXR2 UFD1L CDC45L TSK-p R R Velocardiofacial Syndrome (VCFS) 22q11 DELETION TUPLE N25 Common deletions 87 % 83% 8 % 2% 17% NOT DELETED Slide courtesy of Dr. Christine Finn

  18. Copy Number Variants (CNVs) maternal paternal Typical Locus (CN2) Duplication (CN3) Deletion (CN1) Reviewed in Morrow et al., JAACAP, 2010

  19. Novel Microarrays Allow Facile, Genome-wide Identification of CNVs Bglll digested Microarrays Adaptor ligation Label reference and test DNA and hybridize Genomic DNA PCR amplification (<1.2 kb) Array spotted with computationally designed oligonucleotide probes Modified from: Feuk et al. Nature Reviews Genetics 2006

  20. High-Density SNP Microarrays • 500,000 to 1 million variant SNPs across the arrays • Affymetrix 5.0 or 6.0 • Illumina IM duo • Can be used both for SNP calling and CNV calling. • Please speak with me after class if you want to discuss SNP or CNV calling methods (beyond the scope of today’s lecture).

  21. Causal vs. Common

  22. International Schizophrenia Consortium, Nature, 2008

  23. 15q11 duplications • 1-2% autism • Cook et al., AJHG, 1997 • 0.3% in our study

  24. Recent Example of CNVs and Disorders of Cognitive Development Reviewed in Morrow, JAACAP 2010

  25. Inherited Neurexin-1 hemizygous CNVs are associated with disease. • 6/922 pedigrees (0.6%) • 1/1128 controls (0.08%) • Morrow et al. Science 2008. • Ching et al., AJMG, 2009.

  26. Slide courtesy of David Altshuler MD PhD, Harvard Medical School

  27. X-chromosome variation • 109 variants between any two individuals • 6 were nonrecurrent, including four missense and two synonymous variants • 103 were recurrent, including 40 missense, 60 synonymous and two in-frame insertions/deletions. • The results illustrate that most coding sequence differences between individuals are recurrent (‘common’) variants • a larger number of different nonrecurrent (‘rare’) variants. • How do you know which are associated with disease?

  28. Fragile X syndrome • Most frequent inherited from of ID • Trinucleotide repeat expansion • Associated with ASD in 30%

  29. Genetic Anticipation • Genetic ancipation is a phenomenon wherein symptoms of a genetic condition become more early-onset and severe in new generations of the pedigree.

  30. Gecz et al., 2009

  31. Gecz et al., 2009

  32. What’s the goal of the study? • What’s the approach?

  33. Genes identified in Tarpey et al. • SLC9A6 • BRWD3 • CUL4B • ZDHHC9 • UPF3B • SYP • CASK • How diverse are their functions? • Is their screen saturated?

  34. Summary • ID as a model for genetic heterogeneity • Used large-scale sequencing to identify > 6 disease genes • Used various strategies (linkage and association) to implicate variant with disease • $1000 genome – How will the availability of cost-effective whole-genome sequencing drive personalized medicine and insurance practices?

  35. Autosomal recessive ID • Syndromic • Brain malformations • Metabolic Disorders • Non-Syndromic • PRSS12 • CRBN • CC2D1A Is the screen saturated? How does it compare to X-linked ID?

  36. Metabolic Disorders(Inbred Errors in Metabolism) • Disorders Amino Acid Metabolism (amino acidemias) - • Maple Syrup Urine Disease (MSUD) • Homocystinuria • Disorders of Organic Acid Metabolism (organic acidurias, organic acidemias) - • MethylmalonicAciduria • 3-Methylglutaconic Aciduria – Barth Syndrome • GlutaricAciduria • 2-Hydroxyglutaric aciduria – D and L forms • Disorders of Fatty Acid Beta-Oxidation - • MCAD Deficiency • LCHAD, VLCAD deficiency • Disorders of Lipid Metabolism (lipid storage disorders) - • Gangliosidoses - • GM1 Gangliosidosis • Tay-Sachs Disease • Sandhoff Disease • Sphingolipidoses - • Fabry Disease • Gaucher Disease • Niemann-Pick Disease • Krabbe Disease • Mucolipidoses • Mucopolysaccharidoses • Mitochondrial Disorders - • Mitochondrial cardiomyopathies • Leigh disease • MELAS, MERRF, NARP • Barth syndrome • Peroxisomal Disorders - • Zellweger Syndrome (cerebrohepatorenal syndrome) • X-Linked Adrenoleukodystrophy • Refsum Disease New Rx strategy – enzyme replacement therapy

  37. Treatment for ID • r/o metabolic disorder • Early identification • Educational: • Applied behavioral analysis • Intensive behavioural intervention • No medical treatments for core sx • Psychopharm for behaviour • Developmental Medicine

  38. Developmental Psychopharmacology? • Novel medicines which target processes of synapse maturation • Medicines used as complement to behavioral treatment • Medicines may be administered only during behavioral treatment • Medicines may be time-limited, not life-long

  39. Ethical Issues • Consent • Vulnerable population • Adult population particularly challenging for human subjects research

  40. Future Directions • Diagnosis • Genotype-phenotype correlations • Treatment

  41. AJHG 2010

  42. warning with use of benzos • http://www.idic15.org/Doctors.html

  43. Next-Generation Sequencing • Clinical whole genome sequencing will solve ID.

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