Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders

Abstract

Autism spectrum disorders (ASDs) are a heterogeneous group of neuro-developmental disorders. While significant progress has been made in the identification of genes and copy number variants associated with syndromic autism, little is known to date about the etiology of idiopathic non-syndromic autism. Sanger sequencing of 21 known autism susceptibility genes in 339 individuals with high-functioning, idiopathic ASD revealed de novo mutations in at least one of these genes in 6 of 339 probands (1.8%). Additionally, multiple events of oligogenic heterozygosity were seen, affecting 23 of 339 probands (6.8%). Screening of a control population for novel coding variants in CACNA1C, CDKL5, HOXA1, SHANK3, TSC1, TSC2 and UBE3A by the same sequencing technology revealed that controls were carriers of oligogenic heterozygous events at significantly (P < 0.01) lower rate, suggesting oligogenic heterozygosity as a new potential mechanism in the pathogenesis of ASDs.

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

“…Two recent studies further support the theory of the 'two-hit model' in individuals with ASDs. 19,47 The next challenge in ASDs is therefore to understand the interactions between rare CNVs and other rare variants in individual patients and to take into account environmental interactions that may also modulate the risk for developing ASD. 48 …”

“…12,18 Recent studies point to polygenic or oligogenic inheritance. 6,17,19 Indeed, most of the abnormalities identified have been associated with highly variable phenotypes and seem insufficient to cause ASDs on their own. It is probable that genetic interactions (epistasis) between rare variants have an important role in the etiology of ASDs.…”

A genetic model for neurodevelopmental disease

“…This indicates that they are, by themselves, insufficient to determine disease outcome [1,60]. The mechanisms for this variable expression are not clear but there is compelling evidence of an oligogenic model where multiple rare private variants of moderate to large effect compound to determine final phenotypic outcome [52,60,61]. This model is perhaps strongest for the 16p12.1 microdeletion.…”

Mutations in the C-terminus of CDKL5: proceed with caution

“…Nevertheless, milder phenotypes have been associated with sequence variations in the C-terminus of the CDKL5 gene, described by the authors as potential mutations. [2][3][4] These potential mutations were identified in patients carrying mutations inherited from either the mother or the father, and/or in patients with mental retardation of different degrees without regression or further symptoms. 4 On the other hand, three independent groups have recently identified novel CDKL5 transcripts coding isoforms characterized by an altered C-terminal region.…”

“…[2][3][4] These potential mutations were identified in patients carrying mutations inherited from either the mother or the father, and/or in patients with mental retardation of different degrees without regression or further symptoms. 4 On the other hand, three independent groups have recently identified novel CDKL5 transcripts coding isoforms characterized by an altered C-terminal region. [5][6][7] This finding strongly questions the eventual pathogenicity of sequence variations located in the C-terminus of the gene.…”