Abstract
Nance-Horan syndrome (NHS) is a rare X-linked developmental disorder caused mainly by loss of function variants in the NHS gene. NHS is characterized by congenital cataracts, dental anomalies, and distinctive facial features, and a proportion of the affected individuals also present intellectual disability and congenital cardiopathies. Despite identification of at least 40 distinct hemizygous variants leading to NHS, genotype-phenotype correlations remain largely elusive. In this study, we describe a Sicilian family affected with congenital cataracts and dental anomalies and diagnosed with NHS by whole-exome sequencing (WES). The affected boy from this family presented a late regression of cognitive, motor, language, and adaptive skills, as well as broad behavioral anomalies. Furthermore, brain imaging showed corpus callosum anomalies and periventricular leukoencephalopathy. We expand the phenotypic and mutational NHS spectrum and review potential disease mechanisms underlying the central neurological anomalies and the potential neurodevelopmental features associated with NHS.
Highlights
Genetic brain developmental disorders with associated psychomotor regression include a broad variety of monogenic conditions with expanding clinical differential diagnosis, genetic heterogeneity, and associated disease mechanisms [1,2,3]
Nance-Horan syndrome (NHS) is caused by mutations in the NHS gene located on Xp22.13 [21], which is expressed in the midbrain, retina, lens, and tooth [22,23]
Based on the STRING data (see: https://string-db.org), NHS protein is predicted to interact with a number of other proteins, some of which are encoded by genes already implicated in neurodevelopmental disorders sometimes associated with regressive features (CDKL5, TRAF7)
Summary
Genetic brain developmental disorders with associated psychomotor regression include a broad variety of monogenic conditions with expanding clinical differential diagnosis, genetic heterogeneity, and associated disease mechanisms [1,2,3]. Defining the full spectrum of disease-causing molecular pathways underlying neurodevelopmental disorders will help to diagnose and monitor developmental trajectories in children affected with these conditions [6,7,8,9,10,11]. We report a hemizygous stop mutation in the NHS gene (NM_001291867.2:c.375C>A; p.(Cys125Ter) detected by whole exome sequencing (WES). In a Sicilian boy affected with congenital bilateral cataracts and dental anomalies who displayed regressive brain developmental disorders with impairment of cognition and motor abilities in late childhood; brain imaging showed corpus callosum anomalies and periventricular leukoencephalopathy. This study further highlights the importance of WES in the diagnostic work-up of monogenic bilateral congenital cataracts
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