BACKGROUND For more than a decade, risk stratification for hypertrophic cardiomyopathy has been enhanced by targeted genetic testing. Using sequencing results, clinicians routinely assess the risk of hypertrophic cardiomyopathy in a patient’s relatives and diagnose the condition in patients who have ambiguous clinical presentations. However, the benefits of genetic testing come with the risk that variants may be misclassified. METHODS Using publicly accessible exome data, we identified variants that have previously been considered causal in hypertrophic cardiomyopathy and that are overrepresented in the general population. We studied these variants in diverse populations and reevaluated their initial ascertainments in the medical literature. We reviewed patient records at a leading genetic-testing laboratory for occurrences of these variants during the near-decade-long history of the laboratory. RESULTS Multiple patients, all of whom were of African or unspecified ancestry, received positive reports, with variants misclassified as pathogenic on the basis of the understanding at the time of testing. Subsequently, all reported variants were recategorized as benign. The mutations that were most common in the general population were significantly more common among black Americans than among white Americans (P<0.001). Simulations showed that the inclusion of even small numbers of black Americans in control cohorts probably would have prevented these misclassifications. We identified methodologic shortcomings that contributed to these errors in the medical literature. CONCLUSIONS The misclassification of benign variants as pathogenic that we found in our study shows the need for sequencing the genomes of diverse populations, both in asymptomatic controls and the tested patient population. These results expand on current guidelines, which recommend the use of ancestry-matched controls to interpret variants. As additional populations of different ancestry backgrounds are sequenced, we expect variant reclassifications to increase, particularly for ancestry groups that have historically been less well studied. (Funded by the National Institutes of Health.)

KCNJ8 (NM_004982) encodes the pore forming subunit of one of the ATP-sensitive inwardly rectifying potassium (KATP) channels. KCNJ8 sequence variations are traditionally associated with J-wave syndromes, involving ventricular fibrillation and sudden cardiac death. Recently, the KATP gene ABCC9 (SUR2, NM_020297) has been associated with the multi-organ disorder Cantú syndrome or hypertrichotic osteochondrodysplasia (MIM 239850) (hypertrichosis, macrosomia, osteochondrodysplasia, and cardiomegaly). Here, we report on a patient with a de novo nonsynonymous KCNJ8 SNV (p.V65M) and Cantú syndrome, who tested negative for mutations in ABCC9. The genotype and multi-organ abnormalities of this patient are reviewed. A careful screening of the KATP genes should be performed in all individuals diagnosed with Cantú syndrome and no mutation in ABCC9.

Identification of common molecular pathways affected by genetic variation in autism is important for understanding disease pathogenesis and devising effective therapies. Here, we test the hypothesis that rare genetic variation in the metabotropic glutamate-receptor (mGluR) signaling pathway contributes to autism susceptibility. Single-nucleotide variants in genes encoding components of the mGluR signaling pathway were identified by high-throughput multiplex sequencing of pooled samples from 290 non-syndromic autism cases and 300 ethnically matched controls on two independent next-generation platforms. This analysis revealed significant enrichment of rare functional variants in the mGluR pathway in autism cases. Higher burdens of rare, potentially deleterious variants were identified in autism cases for three pathway genes previously implicated in syndromic autism spectrum disorder, TSC1, TSC2, and SHANK3, suggesting that genetic variation in these genes also contributes to risk for non-syndromic autism. In addition, our analysis identified HOMER1, which encodes a postsynaptic density-localized scaffolding protein that interacts with Shank3 to regulate mGluR activity, as a novel autism-risk gene. Rare, potentially deleterious HOMER1 variants identified uniquely in the autism population affected functionally important protein regions or regulatory sequences and co-segregated closely with autism among children of affected families. We also identified rare ASD-associated coding variants predicted to have damaging effects on components of the Ras/MAPK cascade. Collectively, these findings suggest that altered signaling downstream of mGluRs contributes to the pathogenesis of non-syndromic autism.