Update on the Genetics of Autism and Rett syndrome

Transcription

1 Update on the Genetics of Autism and Rett syndrome Mark E. S. Bailey Lecturer in Molecular Genetics Molecular Genetics, FBLS University of Glasgow

2 Research interests Mental design features in human evolution Genetics of complex disorders of the mind schizophrenia Genetics/mol. biol./mol. pathol. of neurological disorders / conditions Rett syndrome Ménière disease Nerve damage and neuronal regeneration Genetics of physical traits and disease predisposition Evolution of gene families

3 Genetic disorders familial, single gene, Mendelian, dominant/recessive one gene is enough -> affected (= high penetrance ) sporadic, complex, polygenic, multifactorial inheritance multiple genes, environment, interactions we each inherit unique mix of predisposing and protective gene variants > predisposing variants => cross threshold become affected each gene contributes a little to the predisposition (but with low penetrance) >3000 known genetic disorders involving/affecting neurons see OMIM (Online Mendelian Inheritance in Man) website: >700 - genetic cause has been identified mutations identified in known or novel genes several more discovered every month

4 Lumpers and splitters, classification and nosology How do autism and Rett syndrome relate? How do they fit into current understanding of brain dysfunction Here s one way to classify genetic disorders of the CNS/PNS Think in terms of the life cycle of a neuron. Neurodevelopmental Post-devel. Birth Migration Differentiation Maturation Mature functioning Death

5 early development neural induction neural tube defects spina bifida morphogenesis schizencephaly, holoprosencephaly neurogenesis microcephaly migration of neurons Miller-Dieker lissencephaly periventricular heterotopia

6 maturation of neurons and networks neuronal differentiation glycosylation disorders growth and targeting of axons Kallman syndrome - anosmia, hypogonadism growth and maturation of dendritic trees Rett syndrome Synaptogenesis, synapse pruning and network behaviour schizophrenia, autism, Rett syndrome most complex disorders??? mature function channelopathies - ion channel gene mutations epilepsies hemiplegic migraine episodic ataxia fragile X syndrome Angelman syndrome - imprinting disorders Many complex disorders - schizophrenia, bipolar, autism, panic disorder, personality disorders?

7 Degenerative disorders disorders can primarily affect neurons motor neurone disease, spinal muscular atrophy, Parkinson disease peripheral neuropathies - Charcot-Marie-Tooth Glia (neurons affected secondarily) demyelination disorders - multiple sclerosis autoimmune aetiology metabolic storage disorders adrenoleukodystophy ( Lorenzo s Oil ) polyglutamine disorders - trinucleotide repeat expansions Huntington disease spinocerebellar ataxias (SCA) mitochondrial disorders

8 Autism spectrum disorders (ASD) - the clinical picture Dimensions social interaction dysfunction Communication dysfunction language dysfunction repetitive/stereotyped/limited range behavioural repertoire/focus cogn. delay/mr/ld; seizures/syndromes Core psychol. charact c.? - lack of awareness of mental states of others Sally-Anne doll test Extreme male brain?? Diagnosis DSM-IV / ICD-10 6 criteria tot. from 3 dimensions, plus AOO, plus exclusions ADI-R - autism diagnostic interview - revised (2003) 93 Qs, structured parental interview ADOS - autism diagnostic observation schedule Umbrella Pervasive Developmental Disorders Asperger, Childhood Disintegrative Disorder, [Rett syndrome], PDD-NOS

9 Autism Variation severity mix of components final picture almost unique to indiv. Autism spectrum Treatments - Interactive Autism Network (IAN) reports >1,000 different styles in use Speech/Language Therapy OT Applied Behaviour Analysis (ABA) Picture Exchange Communication System (PECS) Social skills groups Sensory Integration Therapy Diet, melatonin, prayer!

10 Autism epidemiology and aetiology Autistic disorder LCI = 0.13% 4:1 Male:Female severe autism 1:1 M:F syndromic autism LCI = ~0.02% 1:1 M:F PDD-NOS LCI = 0.2% Asperger syndrome LCI = 0.03% (3/10,000) 8:1 M:F CDD Rare Some evidence for inc. in incidence over recent decades - ~2-fold Heritability - MZ twin conc. = 70-90%, DZ = 10-25%; H 2 = ~70% Rel. risk to sibs = 22 - all points to strong genetic effects operating Aetiological theories; Idiopathic = genetic OR unknown [response to cold, unemotional mother - thoroughly discredited] NO evidence for MMR vaccination cause Little evidence for mercury exposure cause Reasonable evidence for pre-&peri-natal event risk factors Some evidence for a range of other env. exposure risk factors e.g. rubella, CMV

11 What s wrong in the autistic brain? Some reports of subtle anatomical abnormalities, some with onset prenatally not clear whether field agrees, or how prevalent Cellular dysfunction attributes Synaptic organisation, function Glutamatergic transmission dysfunction? Inhibitory connection dysfunction? Supra-regional dysfunction attributes Reduced hemispheric asymmetry? Long-distance connectivity aberrations? frontal / ant. temporal / parietal connections Mirror neuron activity blunting? Higher-order associations

12 Genetics of Autism and aetiologies Patterns suggest complex Heterogeneity on all sides Env. risk w mild suscept. Oligogenic high pen. Chromo & single gene MF/oligogenic rare or common variant polygenic common variant Environmental influence

13 Searching for autism genes - linkage analysis in familial samples Genome-wide Scan - look for linkage to chromosomal regions across families May find evidence for >1 locus per family set, one per family, some overlap May find evidence for several loci contributing to affected status in one family Follow-up by fine-mapping candidate regions - narrow down critical interval - see what genes localise there turns into candidate gene study mutation screening in affected family members

14 Searching for autism genes - candidate gene association analysis in sporadic samples Many studies start from position of guessing involvement of particular genes Case-control cohort analysis Pick 1 or more genes Genotype variants - e.g. SNPs Single or haplotype-based LD and Tag-SNPs Association analysis Look for overrepresentation of one allele in Cases - O.R. > 1 DRD2 gene risk in alcoholism

15 Searching for autism genes - CNVs Copy Number Variants - newly emerged field since 2006ish genomic loci subject to duplication/deletion type variation each chr. carries 0, 1 or 2 copies each indiv. carries 0, 1, 2, 3 or 4 copies Case-control cohort analysis Pick 1 or more genes Genotype CNV variants Array-based platforms, tricky expts. and interpretn. Flavour of the month!! - overinterpretn?? Look for overrepresentation of CNV alleles in Cases

16 Searching for Autism genes - the GWA scan approach New GWA scan published - Wang et al. Nature, 29/4/09 Genome-wide association study Look at >500,000 SNPs across whole genome in case / control cohort test each for association with disease status focus on SNPs close to each other meeting strict P value threshold P < ish for whole genome data Variants of this strategy - look for association to endo/sub-phenotypes; look at haplotypes and LD

17 What are the genes telling us about autism? Common theme synapse construction and maintenance cell-adhesion molecules Cadherins Neurexins Neuroligins Ubiquitin system Signalling Protein degradation Brain function genes sensitive to dosage CDH10