Secondary findings and carrier test frequencies in a large multiethnic sample

Abstract

BackgroundBesides its growing importance in clinical diagnostics and understanding the genetic basis of Mendelian and complex diseases, whole exome sequencing (WES) is a rich source of additional information of potential clinical utility for physicians, patients and their families. We analyzed the frequency and nature of single nucleotide variants (SNVs) considered secondary findings and recessive disease allele carrier status in the exomes of 8554 individuals from a large, randomly sampled cohort study and 2514 patients from a study of presumed Mendelian disease having undergone WES.MethodsWe used the same sequencing platform and data processing pipeline to analyze all samples and characterized the distributions of reported pathogenic (ClinVar, Human Gene Mutation Database (HGMD)) and predicted deleterious variants in the pre-specified American College of Medical Genetics and Genomics (ACMG) secondary findings and recessive disease genes in different ethnic groups.ResultsIn the 56 ACMG secondary findings genes, the average number of predicted deleterious variants per individual was 0.74, and the mean number of ClinVar reported pathogenic variants was 0.06. We observed an average of 10 deleterious and 0.78 ClinVar reported pathogenic variants per individual in 1423 autosomal recessive disease genes. By repeatedly sampling pairs of exomes, 0.5 % of the randomly generated couples were at 25 % risk of having an affected offspring for an autosomal recessive disorder based on the ClinVar variants.ConclusionsBy investigating reported pathogenic and novel, predicted deleterious variants we estimated the lower and upper limits of the population fraction for which exome sequencing may reveal additional medically relevant information. We suggest that the observed wide range for the lower and upper limits of these frequency numbers will be gradually reduced due to improvement in classification databases and prediction algorithms.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0171-1) contains supplementary material, which is available to authorized users.

A potential founder variant inCARMIL2/RLTPRin three Norwegian families with warts, molluscum contagiosum, and T-cell dysfunction

“…The BCM‐HGSC in‐house database contains exomes from >10,000 individuals (ARIC, Atherosclerosis Risk in Communities) (Gambin et al. ) and from > 5000 individuals with various genetic diseases and their healthy relatives. The Integrative Genomic Viewer (IGV) (Thorvaldsdottir et al.…”

Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals

“…Since the ACMG released their recommendations, several groups have tried to estimate frequencies of actionable variants in 56 genes for diverse samples and by using different methods [10][11][12][13][14][15]. Using WGS or WES data, some studies [15,16] tried to estimate the frequencies of pathogenic variants in the recommended genes for European and African ancestries, and target populations of the 1000 Genomes Project.…”

PEHO Syndrome May Represent Phenotypic Expansion at the Severe End of the Early-Onset Encephalopathies

“…The GNAO1 mutation has not been identified in available mutation databases including Exome Sequencing Project (ESP), 1000 Genomes, Exome Aggregation Consortium (ExAC), and internal Baylor Hopkins Center for Mendelian Genomics database. 8–10 The HESX1 mutation was not recorded in the aforementioned databases except for ExAC where it was found in three of 60,703 individuals, all coming from South Asia (minor allele frequency = 0.00002471). The GNAO1 p.Gly45Glu mutation was predicted to be pathogenic or likely pathogenic by available bioinformatics tools including Sorting Intolerant From Tolerant, MutationTaster, PolyPhen, whereas HESX1 p.Ala9Thr variant was called benign by the same algorithms.…”