A De Novo DHX16 Variant Associated With Neuromuscular Oculoauditory Syndrome Regulates Pre-mRNA Splicing In Vitro

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Molecular Biology

Background:

• Neuromuscular oculoauditory syndrome (NMOAS) is a rare neurodevelopmental disorder.
• It is caused by heterozygous variants in the DHX16 gene, part of the DExD/H-box RNA helicase family.
• The functional impact of DHX16 variants on RNA splicing is not well understood.

Purpose of the Study:

• To investigate the functional impact of a de novo DHX16 variant in a patient with NMOAS.
• To expand the understanding of the genotypic and phenotypic spectrum of DHX16-related NMOAS.
• To explore the role of DHX16 variants in RNA splicing dysregulation.

Main Methods:

• Whole-exome sequencing to identify genetic variants.
• In vitro assays to assess the functional impact of the identified DHX16 variant on RNA splicing.
• Longitudinal clinical follow-up of the affected patient.

Main Results:

• A de novo DHX16 variant (c.1360C>G, p.Arg454Gly) was identified in a patient with NMOAS.
• In vitro assays showed aberrant intron retention in HSPH1 and FOS transcripts, indicating impaired splicing efficiency.
• The patient exhibited progressive multisystem involvement, including delayed gonadal development and autism spectrum disorder phenotypes.

Conclusions:

• The identified DHX16 variant is pathogenic and contributes to splicing dysregulation in NMOAS.
• The study expands the known phenotypic spectrum of NMOAS to include autism spectrum disorder and delayed gonadal development.
• Long-term monitoring for emerging comorbidities in NMOAS patients is crucial.