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Case Reports
. 2023 Apr;14(2):158-163.
doi: 10.1159/000527424. Epub 2022 Dec 23.

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

Cristiana Agazzi  1 , Monia Magliozzi  2 , Onofrio Iacoviello  3 , Stefano Palladino  4 , Maurizio Delvecchio  3 , Maristella Masciopinto  3 , Alessio Galati  3 , Antonio Novelli  2 , Francesco Andrea Causio  5 , Giuseppe Zampino  1 , Claudia Ruggiero  3 , Rita Fischetto  3
Affiliations
Case Reports

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

Cristiana Agazzi et al. Mol Syndromol. 2023 Apr.

Abstract

Introduction: The X-chromosomal USP9X gene encodes a deubiquitylating enzyme involved in protein turnover and TGF-β signaling during fetal and neuronal development. USP9X 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, USP9X missense variants in males often result in partial rather than complete LOF, specifically affecting neuronal migration and development. USP9X 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.

Case presentation: 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 USP9X gene (c.5470A>G, p.Met1824Val) that was never reported in the literature.

Conclusion: We provide an overview of the available literature on USP9X 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 USP9X variants in neuronal development and corroborate the possible association between the novel USP9X variant and congenital heart malformation.

Keywords: Heart defect; Intellectual disability; USP9X; X-linked disorder.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1
Pelvic and hip X-ray highlighting coxa vara on the right side and fragmentation of the head of the femur ipsilaterally.
Fig. 2
Fig. 2
MRI T1, GRE sagittal showing corpus callosum hypoplasia more evident in the isthmus and splenium (<3rd percentiles).
Fig. 3
Fig. 3
MRI T2 coronal (a) and axial sections (b) showing mild ectasia of the lateral and third ventricles.
Fig. 4
Fig. 4
Circle of Willis (3D reconstruction obtained with CT brain angiography). Note the agenesis of the A1 segment of the right anterior cerebral artery and left vertebral artery hypoplasia.
Fig. 5
Fig. 5
USP9X domain structure and location of variants. The variant described in this case report is shown in red.
See this image and copyright information in PMC

References

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