17376
The Genetic Basis of Autism Spectrum Disorders: Identification and Analysis of Rare Structural Variants in a Family Based Study
The genetic causes of autism spectrum disorders (ASDs) are heterogeneous and still unknown in the majority of cases. Structural chromosomal variants (or copy number variants (CNVs) were found in sufficiently high frequency to suggest that cytogenetic and microarray analyses are considered in routine clinical workup. An interesting paradigm for clinical practice is that each rare CNV may account for only a small proportion of variance in ASD at the population level but may have a large effect in a few families in which it segregates.
Objectives:
With this study we aim to contribute to the clinical validation of the current knowledge of ASD risk variants and to the identification of novel variants.
Methods:
CNV association studies are performed in a family based cohort. The sample contains 117 families ascertained through one or more autistic probands with normal intelligence or mild intellectual disability. The study cohort contains 519 individuals: 182 probands, 236 parents, 101 unaffected siblings belonging to 117 families. All probands, unaffected siblings and parents are genotyped with high-resolution Illumina Omni2.5-8v1 microarrays. For all individuals, an extensive list of phenotypic information is collected including IQ, SRS scores, 3DI, clinical genetic examination and family history.
Results:
- The number of causal variants found in ASD patients is highly variable between different studies and depends on the inclusion criteria, array resolution and differences in interpretation due to uncertainty on the true etiological role of particular variants. The strength of this study is a prospective family based approach, with extensive phenotyping and genotyping of all family members.
- In 6,7 % of patients with ASD and normal intelligence a variant that contributes to the ASD phenotype was found.
- In sporadic ASD patients more de novo ASD susceptibility CNVs were detected whereas in familial cases there were more inherited ASD associated variants. These results suggest that currently known ASD susceptibility loci contribute more in sporadic versus familial ASD.
- For a few cases we showed a different etiology for the ASD phenotype in siblings with a large difference in intelligence (proband with normal intelligence and sibling with moderate intellectual disability).
Conclusions:
We present the results of a family based study on the validity of CNV detection in ASD using a high resolution platform. We study the segregation of known and novel rare CNVs with qualitative and quantitative autism phenotypes. Additionally association studies are performed with respect to amongst others gene content and parental origin.