Three Novel de Novo SOX4 Variants Expanding the Phenotypic Spectrum: Case Series and Literature Review

Background: Variants in SOX4 cause intellectual developmental disorder with speech delay and dysmorphic facies (IDDSDF), an autosomal dominant disorder characterized by global developmental delay, mild-to-severe intellectual disability, speech delay, distinctive facial features, digital anomalies, congenital heart defects (unique), and behavioral abnormalities. To date, only a limited number of patients have been described and the phenotypic spectrum of this disorder has yet to be fully delineated. Methods: Clinical data from three patients were collected, including clinical features, growth and developmental profiles, neuropsychological assessments, and urogenital evaluations. Whole-exome sequencing (WES) was performed to screen for candidate variants, and variant pathogenicity was interpreted following the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: All three patients carried previously unreported de novo truncating variants in SOX4: c.583C>T (p.Gln195*), c.1347del (p.Cys450Alafs*5), and c.153G>A (p.Trp51*). Regarding the clinical phenotypes, Patient 3 (P3) was similar to previously reported cases, whereas Patient 1 (P1) and Patient 2 (P2) each exhibited distinctive features on the basis of overlapping with previous reports: P1 presented with severe hypospadias accompanied by cryptorchidism; to our knowledge, no case with this predominant clinical feature has been reported previously. P2 exhibited nystagmus, a novel phenotype not yet reported in the literature. Conclusions: We report three previously unreported de novo truncating variants in SOX4, expand the phenotypic spectrum of SOX4-related disorders to include nystagmus for the first time, and document one patient presenting with severe hypospadias and cryptorchidism. Our findings further expand the mutational and clinical phenotypic spectra of SOX4, underscore the marked clinical heterogeneity of this disorder, and provide new evidence to facilitate clinical recognition and genetic counseling.