Identifying Autism Loci and Genes by Tracing Recent Shared Ancestry

Abstract

To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of “homozygosity mapping” in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations.

No evidence for rare recessive and compound heterozygous disruptive variants in schizophrenia

“…Utilizing populations with recent inbreeding will increase the frequency of these events and the power to detect enrichment, an approach that has been used successfully for CNVs. 20 In conclusion, this sample does not lend support for a major role of disruptive recessive or compound heterozygous variants in the risk of SCZ. There was no overall burden of ROH genome wide or of complete knockout variants exome wide, no specific genomic site was significantly associated and no gene achieved significance after correction.…”

Autism throughout genetics: Perusal of the implication of ion channels

“…The biophysical consequences of this variation are an increase in Na + current and partial channel inactivation (Veeramah et al., 2012; Table 2). In a large study of consanguineous families with autism, a homozygous deletion of SCN7A gene was identified in one family, which is adjacent to SCN1A gene within the sodium channel gene cluster ( SCN1A , SCN2A , SCN3A , and SCN9A ) on chromosome 2 (Morrow et al., 2008; Table 3). …”

Implications of gene copy-number variation in health and diseases

“…On analysis, it was found that this deletion spans 886 kb on chromosome 3q24 affecting DIA1 gene, whose expression level changes in relation to neuronal activity. 31 Schizophrenia Schizophrenia (SZ) is a chronic, debilitating illness with extensive neurological and psychiatric features. Its prevalence is B1% of the population.…”