WDR59 mutations cause early-onset autosomal recessive syndromic dilated cardiomyopathy by dysregulating GATOR2–mTORC1 signaling in six patients.
WDR59 mutations are identified as a novel genetic cause of early-onset autosomal recessive syndromic dilated cardiomyopathy.
Absolute Event Rate: 0% vs 0%
ABSTRACT Pediatric dilated cardiomyopathy (DCM) carries high morbidity and mortality, with up to half of cases genetically unexplained. The mTORC1 nutrient sensing pathway is a critical regulator of cardiomyocyte homeostasis, yet no Mendelian DCM genes have been linked to its upstream regulator, GATOR2. WDR59 encodes a core WD‐repeat subunit of GATOR2, but its cardiac role is unknown. We recruited six affected individuals from four unrelated families presenting with early‐onset, severe autosomal recessive syndromic DCM. Affected children developed left ventricular dilation, variably accompanied by cataracts, dysmorphic facial features, and growth and developmental delay. Saudi patients mapped to a single locus and shared therein a homozygous founder WDR59 variant: c. 2887G>A (p. Gly963Arg). The French patient was compound heterozygous for two variants (NM₀30581. 4: c. 966+3A>G and NM₀30581. 4: c. 886+1219T>G) and their deleterious splicing effect was confirmed by RNA‐seq. We propose WDR59 as a novel autosomal recessive DCM gene and implicate dysregulated GATOR2–mTORC1 signaling as the underlying mechanism. Future validation is needed to confirm this link and investigate whether restoring mTORC1–autophagy balance can ameliorate WDR59 ‐related cardiac dysfunction.
Alabdi et al. (Thu,) reported a other. WDR59 mutations cause early-onset autosomal recessive syndromic dilated cardiomyopathy by dysregulating GATOR2–mTORC1 signaling in six patients.