Balkan Journal of Medical Genetics · Published 2025-12-01 · DOI 10.2478/bjmg-2025-00020
Syndromic X-linked intellectual disability associated with pathogenic variants in HUWE1 includes moderate to severe intellectual disability, dysmorphic features, and epilepsy, and is characterized by clinical variability, especially among carrier females. We present three unrelated symptomatic patients with severe neurodevelopmental symptoms and dysmorphic features, in whom molecular variants c.12469C>G, p.(Leu4157Val); c.5520+4_5520+7del, p.?; and c.4128G>A, p.(Met1376Ile) in the HUWE1 gene were identified. Their phenotypic presentations were consistent with previously reported cases of pathogenic HUWE1 variants. X-chromosome inactivation analysis in blood DNA revealed highly skewed inactivation (97:3) in a female patient, which may help explain the symptomatic course of the disease in her. De novo HUWE1 pathogenic variants in females are frequently associated with a full-blown phenotype. In familial cases, carrier females may be asymptomatic or present mild cognitive impairment, while affected males often exhibit a more severe clinical course. Skewed X-chromosome inactivation may contribute to disease manifestation in female carriers.
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