Key result
A homozygous likely pathogenic c.7645C>T variant in the HERC2 gene was identified in two siblings presenting with severe neurodevelopmental delay and dilated cardiomyopathy.
Why the study?
Loss-of-function HERC2 variants cause severe neurodevelopmental phenotypes, and this report aimed to expand the phenotypic spectrum of HERC2-related disorders to include unusual cardiac manifestations.
Case Report (n=2)
This case report expands the phenotypic spectrum of HERC2-related disorders to include dilated cardiomyopathy, suggesting a potential link between HERC2 dysfunction and cardiac manifestations.
Cardiac evaluation may be warranted in HERC2-related disorders; leaves open whether this novel association is recurrent or requires screening guidelines.
Background: HERC2 encodes an E3 ubiquitin ligase that plays a critical role in brain development. Loss-of-function variants are associated with severe neurodevelopmental phenotypes, including intellectual disability, epilepsy, and various structural anomalies. This report aimed to expand phenotypic spectrum of HERC2-related disorders, including an unusual cardiac manifestation. Case Presentation: The proband, a male infant born to consanguineous parents, presented with myoclonia-like eyelid movements at 50-days old and subsequently developed severe neuromotor regression and choreoathetotic movements. Brain magnetic resonance imaging revealed diffuse cerebral atrophy, corpus callosum thinning, and bilateral pachygyria. He also exhibited distinct dysmorphic features and dilated cardiomyopathy, confirmed by echocardiography. His sibling presented with similar features, including severe developmental delay and dilated cardiomyopathy. Whole-exome sequencing identified a homozygous likely pathogenic c.7645C>T (p.Gln2549Ter) variant in the HERC2 gene. This case report is significant as it describes dilated cardiomyopathy in MRT38, a manifestation not previously associated with HERC2 variants. The unusual cardiac phenotype suggests a potential link between HERC2 dysfunction and mitochondrial impairment, contributing to cardiomyopathy. Conclusion: These patients underscore the importance of recognizing novel clinical features associated with the HERC2 LoF variants, which can guide disease characterization and patient management.
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Şenol et al. (2024) conducted a case report in Autosomal Recessive Intellectual Developmental Disorder-38 and Cardiomyopathy (n=2). Homozygous likely pathogenic c.7645C>T (p.Gln2549Ter) variant in the HERC2 gene was evaluated on Phenotypic spectrum including dilated cardiomyopathy. A homozygous likely pathogenic c.7645C>T variant in the HERC2 gene was identified in two siblings presenting with severe neurodevelopmental delay and dilated cardiomyopathy.
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