Identification of rare DNA sequence variants in high-risk autism families and their prevalence in a large case/control population

Abstract

BackgroundGenetics clearly plays a major role in the etiology of autism spectrum disorders (ASDs), but studies to date are only beginning to characterize the causal genetic variants responsible. Until recently, studies using multiple extended multi-generation families to identify ASD risk genes had not been undertaken.MethodsWe identified haplotypes shared among individuals with ASDs in large multiplex families, followed by targeted DNA capture and sequencing to identify potential causal variants. We also assayed the prevalence of the identified variants in a large ASD case/control population.ResultsWe identified 584 non-conservative missense, nonsense, frameshift and splice site variants that might predispose to autism in our high-risk families. Eleven of these variants were observed to have odds ratios greater than 1.5 in a set of 1,541 unrelated children with autism and 5,785 controls. Three variants, in the RAB11FIP5, ABP1, and JMJD7-PLA2G4B genes, each were observed in a single case and not in any controls. These variants also were not seen in public sequence databases, suggesting that they may be rare causal ASD variants. Twenty-eight additional rare variants were observed only in high-risk ASD families. Collectively, these 39 variants identify 36 genes as ASD risk genes. Segregation of sequence variants and of copy number variants previously detected in these families reveals a complex pattern, with only a RAB11FIP5 variant segregating to all affected individuals in one two-generation pedigree. Some affected individuals were found to have multiple potential risk alleles, including sequence variants and copy number variants (CNVs), suggesting that the high incidence of autism in these families could be best explained by variants at multiple loci.ConclusionsOur study is the first to use haplotype sharing to identify familial ASD risk loci. In total, we identified 39 variants in 36 genes that may confer a genetic risk of developing autism. The observation of 11 of these variants in unrelated ASD cases further supports their role as ASD risk variants.

Using extended pedigrees to identify novel autism spectrum disorder (ASD) candidate genes

“…These findings are consistent with other studies that have also identified multiple genetic etiologies among affected individuals within multiplex ASD pedigrees. For example, Shi et al (2013) identified a number of potentially deleterious rare single-nucleotide variants shared between cases in a two generational multiplex family, and Matsunami et al (2014) identified a complex pattern of segregating SNVs and CNVs in multigenerational ASD pedigrees: crucially, several pedigrees segregated more than one detrimental sequence variant, and among these pedigrees CNVs of potential etiological significance to ASD were also observed. Clearly, therefore, and as demonstrated in our own study, the genetic etiology of ASD in such families is likely complex and not necessarily involving the same genetic mechanisms across closely related cases.…”

Chromosomal Microarray Analysis of Consecutive Individuals with Autism Spectrum Disorders Using an Ultra-High Resolution Chromosomal Microarray Optimized for Neurodevelopmental Disorders

“…We report here on over four years of clinical experience with a real-world referral base for testing on an ultra-high resolution chromosomal microarray specifically designed to extend the scope of detection for individuals with ASD and other neurodevelopmental disorders. This microarray was optimized through the addition of probes targeting genomic regions more recently identified to have pathogenic relevance for DD, ID, and ASD [21,35,36]. …”

ASD Validity

“…However, Matsunami et al (2014) asserted that no single inheritance model for ASD could be correct, because many varied forms of genetic transmission occur with ASD, and Ronemus et al (2014) noted that ASD genetic transmission recurrence risk must vary for families with one child with ASD (simplex) and families with more than one child with ASD (multiplex). An example of varied genetic transmission was reported by Jiang et al (2013), who found multiple varied ASD inheritance patterns in just 16 families: 12 rare X-linked deleterious variants, 7 rare deleterious autosomal-dominant mutations, 13 deleterious missense mutations, and 15 de novo deleterious mutations.…”