Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder of the myocardium characterized by progressive fibrofatty replacement that predisposes to sudden death. Although it classically affects the right ventricle, left and biventricular forms are increasingly recognized. A mutation in one of the 13+ known genes, primarily encoding desmosomal proteins, is found only in half of the patients.
Methods: We identified a family, where the parents were first cousins and four out of four siblings presented in their 2nd or 3rd decade with ventricular tachycardia and cardiomyopathy with progression to cardiac transplantation. Exome sequencing was performed in the proband and filtered for rare (MAF < 1%) protein-altering variants. Illumina HumanOmniExpress BeadChip assay was performed for homozygosity-by-descent mapping. RNA-sequencing of the peripheral blood mononuclear cells was performed to examine the impact of genetic variation on mRNA transcripts.
Results: Gross and histopathologic examination of the three available explanted hearts demonstrated characteristic fibrofatty replacement of ARVC involving predominantly the left ventricle. No mutation was identified in known ARVC genes. Exome sequencing identified 642 rare variants in the proband, including three in the homozygosity-by-descent regions. Among the affected genes, ZBTB17 resides in a region that was previously implicated in dilated cardiomyopathy in European and Han Chinese populations. The ZBTB17 variant alters an essential splice donor site. RNA-sequencing revealed stable expression of the affected intron, which provides evidence for the expression of a truncated protein containing the N-terminal BTB/POZ domain.
Conclusions: Our findings implicate ZBTB17 as a novel gene for ARVC. ZBTB17 (zinc finger and BTB domain containing 17), also known as Miz-1, encodes a zinc finger transcription factor. The BTB/POZ domain truncation protein may alter normal transcriptional activity through loss- or gain-of-function mechanisms. The significance of these findings is to be established experimentally.