Novel Variant in the <b><i>USP9X</i></b> Gene Is Associated with Congenital Heart Disease in a Male Patient: A Case Report and Literature Review

Abstract

<b><i>Introduction:</i></b> The X-chromosomal <i>USP9X</i> gene encodes a deubiquitylating enzyme involved in protein turnover and TGF-β signaling during fetal and neuronal development. <i>USP9X</i> variants in females are primarily associated with complete loss-of-function (LOF) alleles, leading to neurodevelopmental delay and intellectual disability, as well as a wide range of congenital anomalies. In contrast, <i>USP9X</i> missense variants in males often result in partial rather than complete LOF, specifically affecting neuronal migration and development. <i>USP9X</i> variants in males are associated with intellectual disability, behavioral disorders, global developmental delay, speech delay, and structural CNS defects. Facial dysmorphisms are found in almost all patients. <b><i>Case Presentation:</i></b> We report the case of an Italian boy presenting dysmorphism, intellectual disability, structural brain anomalies, and congenital heart disease. Using next-generation sequencing analysis, we identified a hemizygous de novo variant in the <i>USP9X</i> gene (c.5470A&#x3e;G, p.Met1824Val) that was never reported in the literature. <b><i>Conclusion:</i></b> We provide an overview of the available literature on <i>USP9X</i> variants in males, in order to further expand the genotypic and phenotypic landscape of male-restricted X-linked mental retardation syndrome. Our findings confirm the involvement of <i>USP9X</i> variants in neuronal development and corroborate the possible association between the novel <i>USP9X</i> variant and congenital heart malformation.