DHX16-Associated Neuromuscular Oculoauditory Syndrome: A Novel Case

DHX16, a member of the DexD/H-box RNA helicase family, facilitates ATP-dependent unwinding of RNA secondary structures. Pathogenic variants cause poor functioning of the spliceosome complex leading to intron retention in gene transcripts. Clinically, it is associated with neuromuscular oculoauditory syndrome (MIM #618733). To date, there are nine published cases. We report a tenth case: a 3-year-old female, initially presented at 7 months of age, with mild developmental delay, ocular anomalies, dysmorphia, and increased infections. An inherited retinal disorder panel identified nondiagnostic variants of uncertain significance. Trio exome sequencing revealed a de novo Likely Pathogenic DHX16 variant, c.692G>C; p.R231P. Published cases of DHX16-related disorders report developmental delay/intellectual disability, seizures, myopathy, retinal anomalies, myopia, nystagmus, and hearing loss. No published variants to date are located upstream of the start of the helicase domain, and little is known about upstream domains. In silico analysis demonstrates evidence of pathogenicity, while Missense3D modeling demonstrates no structural damage to the protein. These findings are consistent with current literature, suggesting a mechanism of pathogenicity that is difficult to assess via modeling. This case illustrates a DHX16 variant in an unknown domain displaying a mild phenotype.