Haixia Miao

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.

Silver–Russell syndrome (SRS) is most commonly caused by epigenetic alterations at 11p15.5 or maternal uniparental disomy of chromosome 7 [upd(7)mat], though other molecular mechanisms remain unclear. While microdeletions encompassing MEST have been associated with SRS-like phenotypes, no pathogenic intragenic MEST variants have been reported to date. We describe a 6-month-old male infant with clinical features suggestive of a SRS-like phenotype, including intrauterine and postnatal growth restriction, triangular facies, prominent forehead, and small extremities. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) revealed neither methylation abnormalities at 11p15.5, 7p13, or 7q32 nor copy number variations (CNVs) in these regions. Trio whole-exome sequencing (trio-WES) identified a paternally inherited splice-site variant (c.890 + 1G > A) in MEST. Given the paternal-specific expression of MEST, this variant resides on the functionally active allele. Based on in silico predictions and clinical correlation, this case identifies MEST as a plausible candidate gene for SRS and provides a rationale for further functional studies. Phenotypic variation exists across molecular subtypes, yet definitive genotype–phenotype correlations await larger, systematically ascertained cohorts.

Objective: To investigate the clinical characteristics, inheritance patterns, and genotype–phenotype correlations of DHX37 variants in 46,XY disorders of sex development (DSD). Methods: We retrospectively reviewed 108 patients with 46,XY karyotype who underwent DSD evaluation and trio-based whole-exome sequencing (trio-WES) at our center between January 2021 and December 2025. Six probands with DHX37 variants and no concurrent pathogenic or likely pathogenic variants in other known DSD-associated genes were analyzed in detail. Clinical presentations, endocrine profiles, imaging findings, and pedigree data were collected. Variant segregation was confirmed by Sanger sequencing; variants were assessed using in silico prediction, conservation analysis, and structural modeling, and were classified according to ACMG/AMP guidelines. Results: The six probands exhibited marked phenotypic heterogeneity, with manifestations ranging from complete gonadal dysgenesis to mild testicular underdevelopment with gynecomastia. Six heterozygous DHX37 missense variants were identified across distinct functional domains: one in RecA1 [c.1000C>T (p.Arg334Trp)], four in RecA2 [c.1379T>C (p.Val460Ala), c.1432G>A (p.Gly478Arg), c.1730A>G (p.Asp577Gly), and c.1954G>A (p.Val652Ile)], and one in the linker region proximal to the HA2 domain [c.2180C>T (p.Thr727Met)]. Of these, p.Arg334Trp is an established pathogenic variant; p.Gly478Arg has been reported previously, albeit in the same patient included in the present study; and the remaining four were novel. According to ACMG/AMP guidelines, p.Arg334Trp was classified as pathogenic, and the remaining five as variants of uncertain significance. Conclusions: This study provides additional case evidence supporting the pathogenicity of p.Arg334Trp and expands the DHX37 variant spectrum. Computational and structural analyses suggest that p.Gly478Arg may underlie the testicular regression syndrome phenotype of the corresponding proband and that the four novel variants may be involved in testicular development. However, these genotype–phenotype correlations remain speculative; larger cohorts and in vitro functional assays are warranted to confirm these associations.

Background: Pathogenic variants in KDM3B have been implicated as the cause of Diets-Jongmans syndrome (DIJOS), an autosomal-dominant disorder characterized by growth retardation, intellectual disability, facial dysmorphism and autism-spectrum disorder. However, only a limited number of cases have been reported. Methods: The general characteristics of four patients were recorded, including clinical features, child development, neuropsychological assessment and therapeutic interventions. Whole exome sequencing (WES) was performed for potential genetic causes and interpretation of variants was performed in accordance with ACMG guidelines. Results: All patients carried de novo variants in the KDM3B gene, namely, c.2832-3C>G, c.1188del p.(Glu397Argfs*21), c.4580T>C p.(Leu1527Pro), and c.3220dup p.(Glu1074Glyfs*48). Unlike other patients with DIJOS who presented with growth retardation, mild to moderate intellectual developmental disorder and facial dysmorphism, our patients mainly presented with growth retardation, while their neurodevelopment was either normal or mildly impaired. In addition, our patients received primarily supportive care. One patient treated with recombinant human growth hormone (rhGH) showed improvement in growth. Conclusions: Our results broaden the mutational spectrum of KDM3B-related disorder and highlight the inter-patient variability of the clinical phenotype. For the first time, we demonstrate that rhGH therapy can partially promote growth, providing novel evidence for genetic counseling.