Objectives: We explored the hypothesis implicating genetic heterogeneity, in which rare highly penetrant mutations (some of which may be de novo) in different genes specific to single families would predispose to these diseases. This is supported by the recent findings that rare and de novo mutations in the NLGN4X, NLGN3, SHANK3 and other synaptic genes are associated with ASD in a small number of families.
Methods: To identify rare damaging variants, we resequenced one hundred X-linked synaptic genes directly in a cohort of 142 ASD individuals.
Results: We found two truncating mutations: a polymorphism in P2RY4 (p.W348X) and a de novo frameshift deletion in the calcium-related gene IL1RAPL1 (I367SfsX6). Moreover, we identified around one hundred rare variants, with more nonsynonymous damaging variants than expected, which suggests the presence of disease-causing mutations. Promising rare variants, predicted to affect protein function or mRNA splicing, were identified in genes encoding proteins involved in various synaptic functions. Some of these genes (e.g., TSPAN7, OPHN1) were already associated with mental retardation (MR).
Conclusions: Our results indicate that large-scale direct resequencing of synaptic candidate genes constitutes a promising approach to dissect the genetic heterogeneity of ASD and to explore the hypothesis that a number of distinct, individually-rare penetrant variants are involved in the genesis of this condition.