Analysis of pathogenic variants from the ClinVar database in healthy people using next-generation sequencing

Abstract

Next-generation sequencing (NGS) became an effective approach for finding novel causative genomic variants of genetic disorders and is increasingly used for diagnostic purposes. Public variant databases that gather data of pathogenic variants are being relied upon as a source for clinical diagnosis. However, research of pathogenic variants using public databases data could be carried out not only in patients, but also in healthy people. This could provide insights into the most common recessive disorders in populations. The study aim was to use NGS and data from the ClinVar database for the identification of pathogenic variants in the exomes of healthy individuals from the Lithuanian population. To achieve this, 96 exomes were sequenced. An average of 42 139 single-nucleotide variants (SNVs) and 2306 short INDELs were found in each individual exome. Pooled data of study exomes provided a total of 243 192 unique SNVs and 31 623 unique short INDELs. Three hundred and twenty-one unique SNVs were classified as pathogenic. Comparison of the European data from the 1000 Genomes Project with our data revealed five pathogenic genomic variants that are inherited in an autosomal recessive pattern and that statistically significantly differ from the European population data.

National Genome Initiatives in Europe and the United Kingdom in the Era of Whole-Genome Sequencing: A Comprehensive Review

“…Recently, first 96 exomes from healthy Lithuanian individuals were sequenced. An average of 42,139 SNPs and 2306 short indels were found in each individual exome together with five pathogenic genomic variants that were inherited in an autosomal recessive pattern and that statistically significantly differed from the European population data from 1KGP [ 48 ].…”

Autosomal recessive hypercholesterolemia: Case report

“…Moreover, the analysis of the carrier status of autosomal recessive disorders within the Lithuanian population revealed a substantial difference in the frequency of pathogenic variants between individuals from our country and other Caucasian populations, conferring to the higher probability of the development of the disorder due to a homozygous genetic alteration. 21,22 The possibility of uniparental (maternal) disomy of the first chromosome in the absence of any confirmation of the carrier status of the father's variant was rejected both clinically and genetically. The first chromosome, being the biggest chromosome in the genome, should inevitably carry more than one recessive pathogenic variant.…”

Genome rearrangements in neurodevelopmental disorders of the central nervous system: origins, genomic mechanisms, functional and clinical consequences. Review article

“…Ty ri mo me tu bu vo ana li zuo ti uni ka lûs DNR se kos va riantai, at lik ti ið sa mûs mo le ku li niai ty ri mai, ku rie lei do pa tvirtin ti ar at mes ti nu sta ty to va rian to pa to ge nið ku mà. Re miantis ge no ti po ir fe no ti po sà sa jø ana li ziø, duo me nø ba ziø ir li te ra tû ros duo me nø ap þval ga, bu vo at lik tas kli ni ki nis, mo le ku li nis ir (ar) funk ci nis pa to ge ni niø va rian tø cha rakte ri za vi mas [24,25].…”