Abstract 2206: Evidence That Rare Missense Variants Seen in Long QT Syndrome-Susceptibility Genes in Healthy Volunteers Are Not Pathogenic
Introduction: Long QT syndrome (LQTS) is the most common cardiac channelopathy where genetic testing has matured from discovery to translation and now clinical implementation. Whether rare variants found in ostensibly healthy individuals are benign or are low penetrance LQTS-causing mutations has been questioned. We have taken a statistical approach to address this question.
Method: In previous analyses of 1300 ostensibly healthy volunteers including 649 whites and 651 non-whites (blacks, Asians, Hispanics, and others) for the 3 major LQTS genes, 83 missense variants were observed once each. Clinical cases bearing any of these rare control variants were identified in the first 2500 index cases submitted for the FAMILION LQTS genetic test. If these control variants are instead pathogenic, then the yield of “other” mutations in these cases should be dramatically lower than the overall yield of mutations; specifically, it should match the fraction of cases that carry multiple mutations. We therefore contrasted the overall yield and multiple mutation fraction with the yield in these rare-variant-bearing cases.
Results: Of the 83 rare variants, 24 (4 in KCNQ1, 8 in KCNH2, 12 in SCN5A) were observed in 71 of the 2500 cases. Of those 71 cases, 28 (39%) also had a putative mutation not known from controls. This yield is statistically indistinguishable from the 36% overall test yield (p=0.62), but is significantly higher than the 9% (82/903) multiple mutation fraction (p=1.0×10−10).
Conclusions: The results of this study suggest that missense variants seen in even one control should, in the absence of overriding evidence of pathogenicity, be considered background variants of no expected clinical significance in LQTS. A case bearing a rare control variant is no less likely to also have a “real” mutation than a case without such a variant. This statistical result is consistent with our expectations given the rarity of LQTS in the general population, and emphasizes the need to evaluate large healthy reference populations as part of genetic mutation testing.