Biallelic, and not monoallelic, loss of function variants in TRIM63 most likely cause cardiomyopathy
Heterozygous variants in TRIM63 had previously been implicated in cardiomyopathy in humans. However, with the release of large control databases (ExAD and gnomAD) these previously-identified variants were deemed non-disease-causing due to their high population frequencies.
By diagnostic exome sequencing (DES) we identified a patient with cardiomyopathy harboring biallelic loss of function variants in TRIM63, similar to another previously published patient. These patients, combined with evidence from in-vivo studies of knockout mice as well as in-vitro cellular studies, make a strong case to support the notion that biallelic loss of function variants in TRIM63, rather than heterozygous variants, are the cause of cardiomyopathy in humans.
DES is a useful tool for identifying not only novel human disease genes but also for clarifying the mutational mechanism of disease.