Mutation Characteristics in Families with Two or More Siblings with Autism Spectrum Disorder

Background:

Autism spectrum disorder (ASD) is genetically heterogeneous, with >100 susceptibility genes known.

Objectives:

To examine the characteristics of all classes of genetic mutation (small sequence-level changes, structural variation, and copy number variation) in well-characterized ASD-multiplex families by analyzing both de novo and rare inherited mutations.

Methods:

We used whole-genome sequencing (WGS) of 85 quartet families (two parents and two ASD-affected siblings) to comprehensively examine the roles of all classes of mutation in familial ASD.

Results:

In 36/85 (42%) of families, at least one child with ASD had DNA alterations potentially relevant to the disorder. We detected de novo damaging missense and loss-of-function (LoF) single nucleotide and structural mutations in ASD-risk genes in 13/85 (15%) of families. Fifteen additional families carried rare inherited LoF mutations in known ASD-susceptibility genes, and eight more families had de novo or inherited LoF variants in genes associated with autosomal dominant neurodevelopmental disorders. In only one of these families was the same damaging de novo mutation (1.8kb deletion in SCN2A) found in both ASD siblings, but in another 10 families, affected siblings shared inherited ASD-risk variants.

Conclusions:

Taken together, in 11/36 (31%) of families a de novo or rare inherited and presumed penetrant ASD-risk variant(s), identified in the index case, was also found in the sibling with ASD. These siblings tended to be more alike in their phenotypic features than those who did not share a risk variant. In the remaining    families with familial ASD, the siblings carried different mutations, emphasizing the need for WGS in confirmatory and predictive diagnosis.