Targeted Exome Sequencing of Genes Involved in Rare CNVs in Early-Onset Severe Obesity.

Heli Viljakainen,Outi Mäkitie,Päivi Tossavainen,Anna Lindstrand,Petra Loid,Minna Pekkinen,Taina Mustila

doi:10.3389/fgene.2022.839349

Abstract

Context: Rare copy number variants (CNVs) have been associated with the development of severe obesity. However, the potential disease-causing contribution of individual genes within the region of CNVs is often not known. Objective: Screening of rare variants in genes involved in CNVs in Finnish patients with severe early-onset obesity to find candidate genes linked to severe obesity. Methods: Custom-made targeted exome sequencing panel to search for rare (minor allele frequency <0.1%) variants in genes affected by previously identified CNVs in 92 subjects (median age 14 years) with early-onset severe obesity (median body mass index (BMI) Z-score + 4.0). Results: We identified thirteen rare heterozygous variants of unknown significance in eleven subjects in twelve of the CNV genes. Two rare missense variants (p.Pro405Arg and p.Tyr232Cys) were found in SORCS1, a gene highly expressed in the brain and previously linked to diabetes risk. Four rare variants were in genes in the proximal 16p11.2 region (a frameshift variant in TAOK2 and missense variants in SEZ6L2, ALDOA and KIF22) and three rare missense variants were in genes in the 22q11.21 region (AIFM3, ARVCF and KLHL22). Conclusion: We report several rare variants in CNV genes in subjects with childhood obesity. However, the role of the individual genes in the previously identified rare CNVs to development of obesity remains uncertain. More studies are needed to understand the potential role of the specific genes within obesity associated CNVs.

Highlights

Copy number variants (CNVs) are structural variants that include duplications or deletions of genomic regions ranging from 50 bp to several megabases (Zarrei et al, 2015)
It has been proposed that dosage sensitivity of individual genes within the region of CNVs is a frequent cause of CNV pathogenicity
Haploinsufficiency is commonly used as a model of gene dosage sensitivity and predictions of haploinsufficiency have been used to predict the impact of CNVs (Huang et al, 2010; Lek et al, 2016; Rice and McLysaght, 2017)

Summary

Introduction

Copy number variants (CNVs) are structural variants that include duplications or deletions of genomic regions ranging from 50 bp to several megabases (Zarrei et al, 2015). These structural variants can arise by different mutational mechanisms such as replication, repair of double-strand breaks and recombination (Gu et al, 2008; Carvalho and Lupski, 2016). CNVs contribute to human diversity and to several diseases, including neurodevelopmental disorders and severe obesity (Wang et al, 2010; Wheeler et al, 2013; D’Angelo et al, 2018; Saeed et al, 2020). Pathogenic CNVs are usually large and contain genes with high evolutionary copy number conservation. Haploinsufficiency is commonly used as a model of gene dosage sensitivity and predictions of haploinsufficiency have been used to predict the impact of CNVs (Huang et al, 2010; Lek et al, 2016; Rice and McLysaght, 2017)

Methods

Results

Conclusion