Biallelic variants in PPP1R13L cause paediatric dilated cardiomyopathy

Area of Science:

• Genetics
• Cardiology
• Molecular Biology

Background:

• Childhood dilated cardiomyopathy (DCM) is a significant cause of pediatric heart failure, often necessitating cardiac transplantation and carrying a risk of sudden death.
• Identifying genetic causes of DCM is crucial for accurate prognostication, family risk assessment, and guiding clinical management.
• Previous reports suggested a link between PPP1R13L variants and pediatric DCM in a single family.

Purpose of the Study:

• To identify the genetic underpinnings of severe childhood dilated cardiomyopathy.
• To establish a robust gene-disease association for PPP1R13L in pediatric DCM.
• To inform genetic testing strategies for children diagnosed with DCM.

Main Methods:

• Utilized genomic sequencing (exome and genome sequencing) in an international collaborative effort.
• Applied inheritance-based variant filtering to identify causative genetic variants.
• Leveraged GeneMatcher to facilitate family recruitment and data sharing.

Main Results:

• Identified biallelic variants in the PPP1R13L gene in seven children from five unrelated families with severe DCM.
• PPP1R13L encodes the inhibitor of apoptosis-stimulating protein of p53 (iASPP), involved in apoptosis, desmosome regulation, and inflammation.
• The pediatric DCM cases presented early and were progressive, leading to heart transplantation or death.

Conclusions:

• The findings provide strong evidence for a gene-disease association between PPP1R13L and severe pediatric DCM.
• The PPP1R13L gene should be incorporated into genetic testing panels for diagnosing pediatric DCM.
• Genomic sequencing is a powerful tool for discovering novel genetic causes of rare childhood diseases.