Assessment of incidental findings in whole-exome sequences from the Baylor-Hopkins Center for Mendelian Genomics. J. Jurgens1, N. Sobreira1, H. Ling2, E. Pugh2, E. Cirulli3, F. Schiettecatte4, K. Doheny2, A. Hamosh1, D. Valle1 1) Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; 2) Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; 3) Center for Human Genome Variation, Duke University School of Medicine, Durham, NC; 4) FS Consulting, Salem, MA.
As WES and WGS are increasingly utilized, the need to assess the significance of incidental variants is ever more pressing. The ACMG recently published a list of 57 genes implicated in common monogenic disorders with the recommendation that pathogenic and likely pathogenic variants in these genes detected by clinical sequencing be reported. As an initial step in determining the practical consequences of this recommendation, we searched for variants in these genes in the WES data of 55 unrelated probands sequenced in the Baylor-Hopkins Center for Mendelian Genomics. We identified nonsynonymous exonic and splicing variants and indels with MAF < 1% in the 1000 genomes, EVS, and our internal control databases and determined if any of these variants had been described in the HGMD, Emory or ClinVar databases. Our analysis generated a list of 119 variants in 36 (63%) of the 57 genes that passed IGV inspection analysis: 99 missense; 3 nonsense; 15 nonframeshifting indels; and 2 frameshifting indels. 59 variants (50%) were novel. There was a mean of 2.16 variants per individual (range 0 -7); 5 probands had no variants. Of the 119 variants, 44 (37.0%) were listed in HGMD with the prediction that 31 were disease mutations (DM), 10 were uncertain disease mutations (DM?), 2 were disease polymorphisms (DP), and 1 was likely benign (FP). Of these same 44 variants, 2 were in the Emory (with discordant classifications), and 10 were in ClinVar (5 with discordant classifications). 4 variants were listed only in ClinVar. Of the 36 variant-containing genes on the ACMG list, APOB, BRCA2, CACNA1S, DSP, PCSK9, and RYR1 had the most variants (range 7-12/gene) in our 55 probands. Among 1189 controls sequenced at Duke, these genes were found to have rare (<0.5%) functional variants in 2.8%, 29.75%, 21.35%, 33.3%, 12.89%, and 56.34% of the individuals, respectively. Our analysis shows frequent variation in at least some of the 57 genes on the ACMG list with the majority being novel missense mutations not classified in any of the 3 reference databases. Some of these genes are highly mutated in controls. Our result indicates the challenge of assessing the phenotypic consequences of these incidental variants. Analysis of additional WES/WGS data will make interpretation easier, but a single database where variants are uniformly classified with phenotypic information and ongoing review is urgently needed for better interpretation of variants and more accurate counseling of patients.
You may contact the first author (during and after the meeting) at