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

Area of Science:

• Genetics
• Cardiology
• Molecular Biology

Background:

• Pediatric dilated cardiomyopathy (DCM) has high morbidity and mortality, with many cases lacking a genetic explanation.
• The mTORC1 pathway regulates cardiomyocyte function, but its upstream regulators like GATOR2 are not well-understood in Mendelian DCM.
• WDR59, a GATOR2 component, has an unknown role in cardiac health.

Purpose of the Study:

• To identify novel genetic causes of early-onset, severe syndromic DCM.
• To investigate the role of WDR59 in autosomal recessive DCM.
• To explore the link between WDR59 variants, GATOR2, and mTORC1 signaling in cardiac dysfunction.

Main Methods:

• Recruitment of six patients from four families with early-onset, severe syndromic DCM.
• Genetic analysis including locus mapping and whole-exome sequencing to identify WDR59 variants.
• RNA sequencing (RNA-seq) to confirm the deleterious splicing effects of identified variants.

Main Results:

• Identified six individuals with autosomal recessive syndromic DCM linked to WDR59 gene variants.
• Saudi patients shared a homozygous founder variant (c.2887G>A), while a French patient had compound heterozygous variants.
• RNA-seq confirmed deleterious splicing effects of the identified WDR59 variants.

Conclusions:

• WDR59 is proposed as a novel gene implicated in autosomal recessive DCM.
• Dysregulation of the GATOR2-mTORC1 signaling pathway is implicated as the mechanism underlying WDR59-related cardiac dysfunction.
• Further research is needed to validate this link and explore therapeutic strategies targeting mTORC1-autophagy balance.