WDR59 Is Mutated in Individuals With Autosomal Recessive Syndromic Dilated Cardiomyopathy

Biallelic WDR59 variants (GATOR2 subunit), mTORC1 dysregulation and impaired autophagy in cardiomyocytes

6 individuals from 4 unrelated families present with severe early-onset dilated cardiomyopathy and biallelic WDR59 variants. WDR59 is a subunit of the GATOR2 complex, an upstream regulator of the mTORC1 nutrient-sensing pathway. Functional studies in patient cells and cellular models demonstrate mTORC1 dysregulation with impaired autophagy in cardiomyocytes. WDR59 is the first GATOR2 pathway gene implicated in a Mendelian cardiomyopathy.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Identification of WDR59 in DCM opens a direct therapeutic lead via mTORC1 inhibitors (rapamycin and analogues), already used in transplantation. A case to closely follow for geneticists managing unexplained pediatric-onset syndromic DCM, with the prospect of a targeted therapy.

Clinical impact: 2/3 · Evidence strength: 2/3 · Novelty: 2/2 · Sample size: 1/1 · Publication status: 0/1 → Total: 7/10