A Rare Coincidence of Three Inherited Diseases in a Family with Cardiomyopathy and Multiple Extracardiac...

Area of Science:

• Genetics
• Cardiology
• Molecular Biology

Background:

• Genetic diagnosis of primary cardiomyopathies with complex phenotypes remains a challenge.
• A three-generation family presented with cardiomyopathy and diverse extracardiac abnormalities.
• Previous diagnostic efforts for this family had been unsuccessful.

Purpose of the Study:

• To identify the genetic cause of cardiomyopathy and associated extracardiac abnormalities in a multi-generational family.
• To investigate the functional impact of identified genetic variants.
• To demonstrate the utility of comprehensive genetic testing in diagnosing complex, multi-system disorders.

Main Methods:

• Clinical examination of all available family members.
• Whole-exome sequencing (WES) was performed on affected and unaffected individuals.
• Functional studies were conducted to assess the impact of the identified ALPK3 variant on splicing.

Main Results:

• A pathogenic variant (c.4411-2A>C) in the ALPK3 gene was identified in all family members with hypertrophic cardiomyopathy (HCM) or left ventricular hypertrophy (LVH).
• Functional studies confirmed that the ALPK3 variant disrupts canonical splicing.
• Two additional distinct genetic disorders were identified in affected females: a GATA3 variant in the sister and a WDR45 variant in the proband's daughter, explaining their extracardiac manifestations.

Conclusions:

• This study presents a unique case of three monogenic disorders within a single family, highlighting the importance of thorough phenotyping and extensive genetic analysis.
• The findings underscore the role of ALPK3 in familial HCM and provide the first functional evidence of splicing alterations in this gene.
• A comprehensive diagnostic approach integrating clinical data and advanced genetic testing is crucial for achieving precise diagnoses and enabling personalized medicine for complex inherited diseases.