Excess variants in AFF2 detected by massively parallel sequencing of males with autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) is a heterogeneous disorder with substantial heritability, most of which is unexplained. ASD has a population prevalence of one percent and affects four times as many males as females. Patients with fragile X E (FRAXE) intellectual disability, which is caused by a silencing of the X-linked gene AFF2, display a number of ASD-like phenotypes. Duplications and deletions at the AFF2 locus have also been reported in cases with moderate intellectual disability and ASD. We hypothesized that other rare X-linked sequence variants at the AFF2 locus might contribute to ASD. We sequenced the AFF2 genomic region in 202 male ASD probands and found that 2.5% of males sequenced had missense mutations at highly conserved evolutionary sites. When compared with the frequency of missense mutations in 5545 X chromosomes from unaffected controls, we saw a statistically significant enrichment in patients with ASD (OR: 4.9; P < 0.014). In addition, we identified rare AFF2 3' UTR variants at conserved sites which alter gene expression in a luciferase assay. These data suggest that rare variation in AFF2 may be a previously unrecognized ASD susceptibility locus and may help explain some of the male excess of ASD.

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

“…Importantly, a significant excess of rare coding APP , PSEN1 and PSEN2 variants was noted in probands from late-onset Alzheimer disease families even though these variants did not actually co-segregate with the disease; this suggests that the variants in question may nevertheless serve to modulate the risk of disease (Cruchaga et al 2012). An excess of rare variants as compared to controls has also been noted in patients with various other disorders including hypertriglyceridaemia (Johansen et al 2012; Talmud 2007), hypertrophic cardiomyopathy (Lopes et al 2013) and autism spectrum disorder (Mondal et al 2012). …”

Identification of rare X-linked neuroligin variants by massively parallel sequencing in males with autism spectrum disorder

“…Recent reports, in which X-chromosome coding exons in individuals with ASD were sequenced, identified an excess of rare mutations predicted to be damaging in a variety of genes related to synaptic function [16,17]. To date, more than 100 different genes and genomic regions have been linked to this complex trait (see reviews in [18,19]).…”

Peripheral Inflammatory Markers Contributing to Comorbidities in Autism

“…Multiple members of the large family of cytokines are normally produced in the healthy brain where they play critical roles in almost every aspect of neural development, including neurogenesis, migration, differentiation, synapse formation, plasticity, and responses to injury [26,27]. As such, the early cytokine alteration influencing the brain function may identify the onset of developmental disorders like autism as well as underline a particular pattern of disease progression or severity [28,29,30]. …”