Aug 2026· Clinical Genetics· 0 citations· 10 references
Medicine
TL;DR
The genotypic and phenotypic spectrum of NMOAS is expanded, the pathogenic role of this variant in splicing dysregulation is confirmed, and the need for long-term monitoring of emerging comorbidities in affected patients is emphasized.
Abstract
Neuromuscular oculoauditory syndrome (NMOAS; OMIM# 618733) is a rare neurodevelopmental disorder caused by heterozygous variants in DHX16, a gene in the DExD/H-box RNA helicase family. Despite increasing reports of DHX16-related NMOAS, the functional impact of specific variants on RNA splicing remains poorly understood. In this study, whole-exome sequencing identified a de novo DHX16 variant (c.1360C>G, p.Arg454Gly) in a 2-year-old boy with NMOAS. In vitro assays revealed aberrant intron retention in HSPH1 and FOS transcripts in cells expressing the mutant DHX16-1360G, suggesting impaired splicing efficiency. Longitudinal clinical follow-up uncovered progressive multisystem involvement, including delayed gonadal development and autism spectrum disorder phenotypes not previously linked to DHX16. These findings expand the genotypic and phenotypic spectrum of NMOAS, confirm the pathogenic role of this variant in splicing dysregulation, and emphasize the need for long-term monitoring of emerging comorbidities in affected patients.
The findings suggest that PPP1R12A-related disorders may exhibit a broader phenotypic variability than previously recognized and it is proposed that HL and inner ear malformations may represent novel features associated with this clinical spectrum.
G. Pianigiani, Lara Emily Rosso, Anna Morgan et al.· Genes· 0 citations
Pathogenic variation of SLC26A4 gene causes both Pendred syndrome (PDS) and non-syndromic enlarged vestibular aqueduct (NSEVA/DFNB4), two autosomal recessive disorders. The former accounts for approximately 6% of human genetic hearing loss, making it the second most common form of syndromic deafness after Usher syndrome, while the latter is the most common radiological malformation associated with childhood sensorineural hearing loss (SNHL). Here, we used short- and long-read single-cell RNA sequencing (scRNA-seq) of pendrin-expressing cells in the murine cochlea to identify a novel short isoform of Slc26a4. We demonstrate that the short Slc26a4 isoform is expressed in both the inner ear and kidney and investigate its interactions and functions. We also characterize the genotype-phenotype association for SLC26A4-related hearing loss in the context of these two isoforms. These results provide a new reference for molecular profiling of pendrin and offer novel insights into cell-type-specific splicing events and SLC26A4-related hearing loss.
J. Koh, C. Affortit, K. Homma et al.· Human Genetics· 0 citations
This study expands the clinical, genetic, and molecular spectrum of EZH1-associated neurodevelopmental disorders by demonstrating that reduced EZH1 expression is consistent with a loss-of-function disease mechanism.
Mohamed Baity, Khalid K Alharbi, Eman Alobeid et al.· International Journal of Mol...· 0 citations
The findings implicate DCLK1 in a previously unrecognized progressive neurodevelopmental disorder and demonstrate the power of integrative cross-species functional genomics in resolving ultra-rare disease variants.
Stephen C. Pak, David Butler, Wei-Xi Yuan et al.· Research Square· 0 citations