WDR59 Is Mutated in Individuals With Autosomal Recessive Syndromic Dilated Cardiomyopathy.

PMID 41715954 | DOI 10.1111/cge.70151 · Clinical genetics · 2026

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 (NM_030581.4:c.966+3A>G and NM_030581.4: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.