DHX16-Associated Neuromuscular Oculoauditory Syndrome: A Novel Case

Area of Science:

• Genetics and Molecular Biology
• RNA helicases
• Gene regulation

Background:

• DHX16 (DexD/H-box RNA helicase) unwinds RNA secondary structures, crucial for spliceosome function.
• Pathogenic variants lead to intron retention and are associated with neuromuscular oculoauditory syndrome (MIM #618733).
• Previous cases primarily involved variants within or near the helicase domain.

Observation:

• A 3-year-old female presented with mild developmental delay, ocular anomalies, dysmorphia, and recurrent infections.
• Trio exome sequencing identified a de novo likely pathogenic DHX16 variant (c.692G>C; p.R231P) upstream of the helicase domain.
• In silico analysis suggested pathogenicity, but protein structural modeling showed no significant damage.

Findings:

• The identified DHX16 variant (p.R231P) is associated with a mild phenotype in this patient.
• This represents the first reported variant upstream of the helicase domain with unclear functional impact.
• The mechanism of pathogenicity for this variant remains difficult to ascertain through structural modeling.

Implications:

• This case expands the genotypic and phenotypic spectrum of DHX16-related disorders.
• Further research is needed to understand the functional consequences of variants in uncharacterized domains of DHX16.
• Highlights the complexity of predicting pathogenicity based solely on in silico and structural analyses.