Novel USP9X Mutation in A Lebanese Patient with Delay and Microcephaly: Case Report and Review of Literature

Introduction: USP9X gene is located on the X-chromosome and encodes for an enzyme that regulates important substrates involved in neuronal growth and development. Thus, rare USP9X mutations were identified as directly causative of neurodevelopmental disorders (NDDs) and Intellectual Disability (ID) in homozygous males and more rarely in heterozygous females. In males, USP9X variants have been linked to an X-linked mental retardation syndrome that includes; central nervous system (CNS) abnormalities (white matter disturbances, thin corpus callosum, widened ventricles, and cerebellar defects), global delay with significant alteration of speech, language and behavior, hypotonia, joint hypermobility, digital abnormalities, gastro-intestinal symptoms, visual system defects and dysmorphic facial features.

Patient Data: We report the rare case of a 3 years old and 8 months male patient presenting with NDD, ID, speech delay, progressive aggressive behavioral changes and CNS abnormalities (microcephaly, left periventricular lesion). He was found to have a USP9X variant carrying a missense mutation: USP9X, c.1870A>T p.(Met624Leu) on Whole-Exome Sequencing (WES).

Discussion: Our patient had most of the important features of the previously described X-linked mental retardation syndrome but some were absent such as dysmorphic features, digital or visual abnormalities and hypotonia. Microcephaly rather than macrocephaly was noted, which could be an additional potential CNS malformation, expanding the spectrum of phenotypic characteristics of the USP9X variants. No associated congenital anomalies were noted that are usually more common in female subjects.

Conclusion: This is to our knowledge the first reported case of a USP9X variant in Lebanon. The clinical characteristics matched most of the previously described features in the literature. Microcephaly was a new clinical feature not previously described and could be a new possible phenotypic characteristic of the disease.