Secondary findings and carrier test frequencies in a large multiethnic sample

Abstract

Background: Besides 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.

Methods: We 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.

Results: In 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.

Conclusions: By 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.

Fig. 1

Assigned ethnicity by study origin for 8554 ARIC and 2514 CMG individuals

Fig. 2

Distribution of the number of annotated variants per individual in 56 ACMG SF genes. a Rare nonsynonymous variants. b Predicted deleterious variants

Fig. 3

Distribution of the number of reported pathogenic variants per individual in 56 ACMG SF genes according to HGMD-DM (black bars), ClinVar (light gray bars) and combined (dark gray bars) databases

Fig. 4

Distribution of the number of variants per individual in autosomal recessive disease genes. a Rare nonsynonymous variants. b Predicted deleterious variants

Fig. 5

Distribution of the number of reported pathogenic variants per individual in autosomal recessive disease genes according to HGMD-DM (black bars), ClinVar (light gray bars), and combined (dark gray bars) databases

Fig. 6

Distributions of the number of annotated nonsynonymous variants among ethnic groups in 56 ACMG SF genes (a) and in autosomal recessive disease genes (b)