Allelic variants in HTR3C show association with autism.

Autism spectrum disorders (ASDs) are severe neurodevelopmental disorders with a strong genetic component. Only a few predisposing genes have been identified so far. We have previously performed a genome-wide linkage screen for ASDs in Finnish families where the most significant linkage peak was identified at 3q25-27. Here, 11 positional and functionally relevant candidate genes at 3q25-27 were tested for association with autistic disorder. Genotypes of 125 single nucleotide polymorphisms (SNPs) were determined in 97 families with at least one individual affected with autistic disorder. The most significant association was observed using two non-synonymous SNPs in HTR3C, rs6766410 and rs6807362, both resulting in P = 0.0012 in family-based association analysis. In addition, the haplotype C-C corresponding to amino acids N163-A405 was overtransmitted to affected individuals (P = 0.006). Sequencing revealed no other variants in the coding region or splice sites of HTR3C. Based on the association analysis results in a previously identified linkage region, we propose that HTR3C represents a novel candidate locus for ASDs and should be tested in other populations.

Analysis of X chromosome inactivation in autism spectrum disorders.

Autism spectrum disorders (ASD) are complex genetic disorders more frequently observed in males. Skewed X chromosome inactivation (XCI) is observed in heterozygous females carrying gene mutations involved in several X-linked syndromes. In this study, we aimed to estimate the role of X-linked genes in ASD susceptibility by ascertaining the XCI pattern in a sample of 543 informative mothers of children with ASD and in a sample of 163 affected girls. The XCI pattern was also determined in two control groups (144 adult females and 40 young females) with a similar age distribution to the mothers sample and affected girls sample, respectively. We observed no significant excess of skewed XCI in families with ASD. Interestingly, two mothers and one girl carrying known mutations in X-linked genes (NLGN3, ATRX, MECP2) showed highly skewed XCI, suggesting that ascertainment of XCI could reveal families with X-linked mutations. Linkage analysis was carried out in the subgroup of multiplex families with skewed XCI (> or = 80:20) and a modest increased allele sharing was obtained in the Xq27-Xq28 region, with a peak Z-score of 1.75 close to rs719489. In summary, our results suggest that there is no major X-linked gene subject to XCI and expressed in blood cells conferring susceptibility to ASD. However, the possibility that rare mutations in X-linked genes could contribute to ASD cannot be excluded. We propose that the XCI profile could be a useful criteria to prioritize families for mutation screening of X-linked candidate genes.