Functional and clinical implications of genetic structure in 1686 Italian exomes

Abstract

To reconstruct the phenotypical and clinical implications of the Italian genetic structure, we thoroughly analyzed a whole‐exome sequencing data set comprised of 1686 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 American College of Medical Genetics (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 data set 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 data set publicly available as a tool for both clinicians and researchers (http://nigdb.cineca.it; NIG‐ExIT).

Assessing temporal and geographic contacts across the Adriatic Sea through the analysis of genome-wide data from Southern Italy

“…Finally, we found extreme divergence in a region within the EDAR (Ectodysplasin A receptor) gene, associated with variations in head hair morphology and facial hair thickness (52). Although the SNP rs3827760 (chr2:109513601), affecting hair follicle thickness and shape, is not present in our dataset, it is unlikely that it is driving the adaptation signal, as also observed in a previous exome analysis (37).…”

“…The largest degree of genetic heterogeneity across the European continent has been so far recorded in the Italian Peninsula (19), an important aspect to consider when epidemiological and translational studies in Italy are planned. Recent researches taking advantage of high coverage whole-genome and whole-exome sequences linked variants under selection in Italians to genes that were related to insulin secretion, obesity, thermogenesis, alcohol consumption, pathogenic-response, skin colour and cancer (37,38). Here we assessed the occurrence of extreme differences in allele frequencies between Northern and Southern Italy close to the ALDH2, NID1 , and CBLB genes that may have a role in alcohol metabolism, nevi features and immunological traits, respectively.…”

“…Furthermore, a recent aDNA study (35) showed that Iron Age Apulians were not yet superimposable to contemporary Southern Italians, pointing to later processes as keys for the understanding of present-day genetic diversity in Italy. As a consequence of this complex demographic scenario, Italy harbours the largest degree of genetic population structure identified in Europe so far (19,36), making its population a valuable asset for adaptation studies (36)(37)(38). In this study, we performed a genome-wide analysis, unveiling the contemporary genetic structure of present-day South and Eastern European populations, and highlighting recent and past interactions between Southern Italy and Greece.…”

Combination of Genomic and Transcriptomic Approaches Highlights Vascular and Circadian Clock Components in Multiple Sclerosis

“…Based on the higher genetic variability in the Italian population as compared with other European populations [ 95 , 96 ], leading to recommending the use of population-specific databases for a more accurate assessment of variant pathogenicity [ 97 ], we compared populations with MAFs obtained from (i) the Network for Italian Genomes “NIG-IT” which include whole-exome sequencing for 1098 unrelated Italian individuals affected by different diseases, MS included; (ii) Controls from 1000 Genome Project which contains allelic frequencies for a sample of Tuscany, Italy (1000G TSI), an optimal reference population for individuals under study. The low prevalence (188 per 100,000 individuals) of MS in Tuscany [ 98 ] makes improbable the presence of individuals with MS in the Tuscany control sample.…”

Frequency of Parkinson’s Disease Genes and Role of PARK2 in Amyotrophic Lateral Sclerosis: An NGS Study

“…As healthy controls, we used the recently published whole-exome sequencing data set composed of 1686 healthy Italian individuals [ 25 ]. In detail, we selected variants with an allele frequency < 1% and a reported effect that included: missense, synonymous, structural interaction variant, splice variant frameshift variant.…”