Congenital cataracts (CCs) are a leading cause of preventable childhood blindness, with genetic factors playing a crucial role in their etiology. Nance–Horan syndrome (NHS) is a rare X-linked dominant disorder associated with CCs but is often underdiagnosed due to variable expressivity, particularly in
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Congenital cataracts (CCs) are a leading cause of preventable childhood blindness, with genetic factors playing a crucial role in their etiology. Nance–Horan syndrome (NHS) is a rare X-linked dominant disorder associated with CCs but is often underdiagnosed due to variable expressivity, particularly in female carriers.
Objective: This study aimed to explore the genetic landscape of CCs in a Swiss cohort, focusing on two novel
NHS and one novel
GJA8 variants and their phenotypic presentation.
Methods: Whole-exome sequencing (WES) was conducted on 20 unrelated Swiss families diagnosed with CCs. Variants were analyzed for pathogenicity using genetic databases, and segregation analysis was performed. Clinical data, including cataract phenotype and associated systemic anomalies, were assessed to establish genotype–phenotype correlations.
Results: Potentially pathogenic DNA sequence variants were identified in 10 families, including three novel variants, one in
GJA8 (c.584T>C) and two
NHS variants (c.250_252insA and c.484del). Additional previously reported variants were detected in
CRYBA1,
CRYGC,
CRYAA,
MIP,
EPHA2, and
MAF, reflecting genetic heterogeneity in the cohort. Notably,
NHS variants displayed significant phenotypic variability, suggesting dose-dependent effects and X-chromosome inactivation in female carriers.
Conclusions: NHS remains underdiagnosed due to its variable expressivity and the late manifestation of systemic features, often leading to misclassification as isolated CC. This study highlights the importance of genetic testing in unexplained CC cases to improve early detection of syndromic forms. The identification of novel
NHS and
GJA8 variants provides new insights into the genetic complexity of CCs, emphasizing the need for further research on genotype–phenotype correlations.
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