The analysis of rare genomic copy number variants (CNVs) in siblings of a proband (the starting point for a genetic study of a family) with autism spectrum disorder (ASD) could be used to predict the likelihood of developing ASD themselves, according to an article published today in Nature. The study used 253 families with an ASD proband and encompassed a total of 288 infant siblings. They underwent whole genome sequencing to investigate whether CNVs affecting ASD-related loci correlate with phenotypic outcomes of the disorder.

Diagnosing ASD has proven difficult as there are no medical tests that can currently be carried out, such as a blood test. Behavioural assessment remains the gold standard for ASD diagnosis in children and adults, and early intervention to target behaviour and skills development is currently the best way to reduce symptoms. The study adds to the growing evidence that there may be a genetic component of ASD that might contribute to early detection in infants that are likely to develop ASD.

Other currently published research estimate that there is a recurrence rate of 6.8-19.5% in siblings of an ASD proband. It is also estimated up to 30-40% of younger siblings of autistic probands who are not diagnosed with ASD have suboptimal developmental functioning and/or subclinical ASD traits. Current research has also identified CNV loci and ASD-relevant genes that many overlap others associated with different neurodevelopmental disorders.

The study gathered families from The Baby Siblings Research Consortium to use families associated with a higher probability of developing ASD. To consider if a CNV was pathogenic or likely pathogenic, its association with an established genomic disorder of ASD was checked (e.g. 15p11.2 microdeletion) and if it overlapped with an exon of a high-confidence ASD-susceptibility gene (e.g. SHANK3).
The research published today shows that there are indeed some CNVs that can be detected in siblings of ASD probands to predict the development of ASD or atypical development. 15 CNVs were identified in 13 of the 253 probands that were deemed as relevant to developing ASD. Six of these CNVs were considered pathogenic, with seven being clinically defined as variants of unknown significance that overlapped genes implicated in ASD.

Six CNVs in five probands were de novo (three deletions and three duplications). Eight CNVs (five deletions and three duplications) were identified as inherited; one paternally and seven maternally. These inherited CNVs were also found to be shared with an infant sibling, of which four were already diagnosed with ASD and three showed atypical development without a formal ASD diagnosis.

With these results, CNV analysis in siblings of ASD probands could have been predictive pre-symptomatically of the disorder in 11 (5%) of the siblings who were eventually diagnosed clinically. Whilst this number is relatively low, it still provides a starting point for understanding the underlying genetics of ASDs. It could be crucial in informing risk estimates for some families and has the potential to determine which therapeutic intervention those at risk would most benefit from.

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