Functional and clinical implications of genetic structure in 1686 Italian exomes

In order to reconstruct the phenotypical and clinical implications of the Italian genetic structure, we thoroughly analyzed a whole-exome sequencing dataset comprised of 1,686 healthy Italian individuals. We found six previously unreported variants with remarkable frequency differences between Northern and Southern Italy in the HERC2, OR52R1, ADH1B and THBS4 genes. We reported 36 clinically relevant variants (submitted as pathogenic, risk factors or drug response in ClinVar) with significant frequency differences between Italy and Europe. We then explored putatively pathogenic variants in the Italian exome. On average, our Italian individuals carried 16.6 protein-truncating variants (PTVs), with 2.5% of the population having a PTV in one of the 59 ACMG actionable genes. Lastly, we looked for PTVs that are likely to cause Mendelian diseases. We found four heterozygous PTVs in haploinsufficient genes (KAT6A, PTCH1 and STXBP1) and three homozygous PTVs in genes causing recessive diseases (DPYD, FLG and PYGM). Comparing frequencies from our dataset to other public databases, like gnomAD, we showed the importance of population-specific databases for a more accurate assessment of variant pathogenicity. For this reason, we made aggregated frequencies from our dataset publicly available as a tool for both clinicians and researchers (http://nigdb.cineca.it, NIG-ExIT). This article is protected by copyright. All rights reserved.