- De novo DHX16 variant c.1360C>G (p.Arg454Gly) identified by whole-exome sequencing in a 2-year-old with NMOAS.
- Mutant DHX16-1360G causes aberrant intron retention in HSPH1 and FOS transcripts, demonstrating impaired pre-mRNA splicing in vitro.
- Longitudinal follow-up reveals progressive multisystem involvement including delayed gonadal development and autism spectrum disorder features, expanding NMOAS phenotype and surveillance needs.
Clin Genet. 2026 Aug 6. doi: 10.1111/cge.70222. Online ahead of print.
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.
PMID:42562406 | DOI:10.1111/cge.70222
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