DNAJC3-Related Syndromic Monogenic Diabetes Without Clinically Evident Neurological Manifestations in an Adult: Expanding the Phenotypic Spectrum.

PMID 42353846 | PMCID PMC13299322 | DOI 10.3390/genes17060687 · Genes · 2026 · View on PubMed ↗

Background/Objectives: DNAJC3-related syndromic monogenic diabetes is a rare autosomal recessive disorder that presents as juvenile-onset non-autoimmune diabetes; it has been associated with sensorineural hearing loss, hypothyroidism, short stature, and variable degrees of neurological manifestations. A delayed diagnosis occurs frequently because of fragmented subspecialty care and lack of awareness of syndromic monogenic diabetes. Methods: We report a 34-year-old Saudi male from a consanguineous family with insulin-treated diabetes diagnosed during adolescence. He had long-standing sensorineural hearing loss, hypothyroidism, and short stature, which were managed separately. Results: Genetic analysis using whole-exome sequencing identified a homozygous likely pathogenic DNAJC3 variant, c.1177C>T p.(Arg393*), confirming the diagnosis of DNAJC3-related syndromic monogenic diabetes. In addition, he demonstrated no clinically evident neurological manifestations at the time of evaluation, including ataxia, despite reaching adulthood, highlighting the phenotypic variability associated with DNAJC3-related disease. Conclusions: This case adds to the growing evidence supporting phenotypic variability in DNAJC3-related syndromic monogenic diabetes by describing an adult presentation without clinically evident neurological manifestations at the time of evaluation. It highlights how systemic manifestations may remain unrecognized when managed separately across different specialties. In individuals with atypical diabetes accompanied by multisystem involvement, particularly in the setting of consanguinity, early consideration of monogenic diabetes and timely genetic testing may facilitate accurate diagnosis and molecular classification. Establishing a specific genetic diagnosis supports appropriate genetic counseling, informs reproductive decision-making, and may help reduce prolonged diagnostic uncertainty.