Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes

Abstract

Aim Severe mental illnesses (SMI), such as bipolar disorder and schizophrenia, are highly heritable, and have a complex pattern of inheritance. Genome‐wide association studies detect a part of the heritability, which can be attributed to common genetic variation. Examination of rare variants with next‐generation sequencing may add to the understanding of the genetic architecture of SMI. Methods We analyzed 32 ill subjects from eight multiplex families and 33 healthy individuals using whole‐exome sequencing. Prioritized variants were selected by a three‐step filtering process, which included: deleteriousness by five in silico algorithms; sharing within families by affected individuals; rarity in South Asian sample estimated using the Exome Aggregation Consortium data; and complete absence of these variants in control individuals from the same gene pool. Results We identified 42 rare, non‐synonymous deleterious variants (~5 per pedigree) in this study. None of the variants were shared across families, indicating a ‘private’ mutational profile. Twenty (47.6%) of the variant harboring genes were previously reported to contribute to the risk of diverse neuropsychiatric syndromes, nine (21.4%) of which were of Mendelian inheritance. These included genes carrying novel deleterious variants, such as the GRM1 gene implicated in spinocerebellar ataxia 44 and the NIPBL gene implicated in Cornelia de Lange syndrome. Conclusion Next‐generation sequencing approaches in family‐based studies are useful to identify novel and rare variants in genes for complex disorders like SMI. The findings of the study suggest a potential phenotypic burden of rare variants in Mendelian disease genes, indicating pleiotropic effects in the etiology of SMI.

A novel microduplication in INPP5A segregates with schizophrenia spectrum disorder in the family of a patient with both childhood onset schizophrenia and autism spectrum disorder

“…rs751524528 (p.A80V) is a benign non‐synonymous mutation (according to Polyphen2) in a 31‐year‐old female affected by adult‐onset schizoaffective disorder (bipolar type) without developmental delays, mental retardation, and learning disabilities (Xu et al, 2011). rs775793924 (p.R168W) is a rare SNV defined by authors as a «non‐synonymous damaging strict and disruptive» variant and was found in a multiplex family with subjects affected by bipolar disorder or SSD with no phenotypic description (Ganesh et al, 2019). Finally, an epigenome‐wide significant ( p < 1.7 × 10 −8 ) association for phonemic verbal fluency (cg12507869, p = 2.5 × 10 −9 ) was found in an epigenome‐wide association study.…”

Targeted Sequencing Detects Variants That May Contribute to the Risk of Neuropsychiatric Disorders

“…These rare variants may be shared within family members. 6 Hence, the study of rare variants of moderate-to-large effects becomes important, as they may highlight the dysfunction of disease-associated pathways.…”

Analysis of whole exome sequencing in severe mental illness hints at selection of brain development and immune related genes

“…As described in our previous study 59 , whole exome sequencing was carried out on the Illumina Hiseq NGS platform with libraries prepared using Illumina exome kits. Reads were aligned with the reference human genome hg19 using the Burrows-Wheeler algorithm tool (https://academic.oup.com/bioinformatics/article/25/14/1754/225615).…”