Key result
Compound heterozygous recessive mutations in TAF1A were identified as the cause of idiopathic end-stage heart failure in two sisters, expanding the spectrum of ribosomopathies to pediatric DCM.
Case Report (n=2)
Recessive mutations in TAF1A expand the clinical spectrum of ribosomopathies to include pediatric dilated cardiomyopathy.
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TAF1A testing may be considered in familial pediatric DCM; extends ribosomopathy spectrum but remains hypothesis-generating.
Non-ischemic dilated cardiomyopathy (DCM) has been recognized as a heritable disorder for over 25 years, yet clinical genetic testing is non-diagnostic in >50% of patients, underscoring the ongoing need for DCM gene discovery. Here, whole exome sequencing uncovered a novel molecular basis for idiopathic end-stage heart failure in two sisters who underwent cardiac transplantation at three years of age. Compound heterozygous recessive mutations in TAF1A, encoding an RNA polymerase I complex protein, were associated with marked fibrosis of explanted hearts and gene-specific nucleolar segregation defects in cardiomyocytes, indicative of impaired ribosomal RNA synthesis. Knockout of the homologous gene in zebrafish recapitulated a heart failure phenotype with pericardial edema, decreased ventricular systolic function, and embryonic mortality. These findings expand the clinical spectrum of ribosomopathies to include pediatric DCM.
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Long et al. (2017) conducted a case report in Pediatric dilated cardiomyopathy (n=2). Whole exome sequencing was evaluated on Molecular basis for idiopathic end-stage heart failure. Compound heterozygous recessive mutations in TAF1A were identified as the cause of idiopathic end-stage heart failure in two sisters, expanding the spectrum of ribosomopathies to pediatric DCM.
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