Phenomic determinants of genomic variation in autism spectrum disorders.
J Med Genet
; 46(10): 680-8, 2009 Oct.
Article
in En
| MEDLINE
| ID: mdl-19625284
ABSTRACT
BACKGROUND:
Autism spectrum disorders (ASDs) are common, heritable neurobiologic conditions of unknown aetiology confounded by significant clinical and genetic heterogeneity.METHODS:
This study evaluated a broad categorisation of phenotypic traits (or phenome) for 100 subjects with Autism Diagnostic Interview-Revised/Autism Diagnostic Observation Schedule-Generic (ADI-R/ADOS-G) confirmed idiopathic ASD undergoing 1 Mb bacterial artificial chromosome (BAC) array comparative genomic hybridisation (CGH). RESULTS ANDCONCLUSIONS:
Array CGH uncovered nine different pathogenic copy number variants (pCNVs) in 9/100 ASD subjects having complex phenotypes (ASD+/- intellectual disability (ID; IQ<70)) and/or physical anomalies), normal karyotype, fragile X analysis, and comprehensive evaluation by a clinical geneticist. Unique pCNVs in our cohort included del(5)(p15.2p15.31) (2.4 Mb), del(3)(p24.3) (0.1 Mb) and dup(18)(p11.3)(0.9 Mb). Five pCNVs were recurrent in our cohort or were previously described in subjects with ASD+/-ID (dup(7)(q11.23)(1.5 Mb); del(2)(p15p16.1) (6.1 Mb and 7.9 Mb); del(14)(q11.2) (0.7 Mb) and dup(15)(q11q13) (10 Mb), including del(X)(p11.22) (470 Kb) in two autistic brothers. Male female distribution in subjects with pCNVs was reduced to 1.251 from 3.21 in the original cohort. The authors stratified the study population according to a broad spectrum of clinical features and correlated specific phenotypes with respect to CNV load and pathogenicity. The findings indicate increased prevalence of pCNVs in subjects with microcephaly (<2nd centile; n = 2 of 4 ASD subjects with microcephaly; p = 0.04), and ID (n = 9 of 64 subjects with ASD and ID; p = 0.02). Interestingly, in the absence of ID co-morbidity with an ASD, no pCNVs were found. The relationship between parental ages at delivery and CNV load and pathogenicity was also explored.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Genetic Variation
/
Child Development Disorders, Pervasive
Type of study:
Etiology_studies
/
Incidence_studies
/
Observational_studies
/
Risk_factors_studies
Limits:
Adolescent
/
Adult
/
Child
/
Child, preschool
/
Female
/
Humans
/
Male
Language:
En
Journal:
J Med Genet
Year:
2009
Document type:
Article
Affiliation country:
Canada
Publication country:
ENGLAND
/
ESCOCIA
/
GB
/
GREAT BRITAIN
/
INGLATERRA
/
REINO UNIDO
/
SCOTLAND
/
UK
/
UNITED KINGDOM