Predictive Impact of Rare Genomic Copy Number Variations in Siblings of Individuals with Autism Spectrum Disorders

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Predictive Impact of Rare Genomic Copy Number Variations in…

Behavioral assessments remain the gold standard for autism spectrum disorder (ASD) diagnosis, and prospective analysis permits objective and longitudinal assessment for the earliest symptoms. Published estimates of sibling recurrence for ASD range from 6.9 to 19.5%. Moreover, of younger siblings of autistic probands, herein referred to simply as “infant siblings”, who are not diagnosed with ASD, up to 30–40% have subclinical ASD traits and/or suboptimal developmental functioning.

ASD and related subclinical traits show familial clustering, with a substantial portion of familial liability attributed to genetic factors. Subclinical symptoms in first- and second-degree relatives support an important role for genetic factors in producing an autistic phenotype9. The genetic architecture of ASD is being resolved by studying families with different characteristics, and dozens of copy number variant (CNV) loci and ASD-relevant genes and loci are known, many of which overlap those associated with other neurodevelopmental disorders. De novo and inherited rare (<1% in a population) CNVs and other pathogenic variants are found in ~ 5–40% of individuals with ASD, depending on the cohort examined. Chromosomal microarray to detect CNVs is the first-tier laboratory test for clinical genetic evaluation following an ASD diagnosis.

The most effective way to reduce symptoms of ASD is with early intervention, targeting behavior, and skills development. In search of biomarkers for early identification, we investigated whether CNVs affecting ASD-related loci correlate (pre- and post-symptomatically) with phenotypic outcomes in the Baby Siblings Research Consortium (BSRC) cohort of infant siblings whose family history is associated with a higher probability of developing ASD (Fig. 1). We analyze CNVs from 253 families registered in the BSRC24 while blinded to the infant siblings’ phenotype status. At enrollment, each family included a proband diagnosed with ASD, and at least 1 younger sibling (Supplementary Table 1). The BSRC longitudinal phenotyping design enables a predictive study of CNVs in this infant cohort (see Methods). Our analyses reveal that the detection of ASD-relevant CNVs is indeed predictive of ASD or atypical development in this sibling population and can be used to inform risk estimates for individuals and their families, with potential impact on their therapeutic trajectory.  Read more . . .

D’Abate, L., Walker, S., Yuen, R.K.C. et al. Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders. Nat Commun 10, 5519 (2019).