**Background:** Diabetes mellitus (DM) in children and adolescents is typically caused by type 1 DM, type 2 DM, or maturity-onset diabetes of the young (MODY). This report describes an unusual Asian Indian family in which three members presented with DM at ages 15, 20, and 30, without fitting typical clinical pictures. The primary objective was to elucidate the molecular genetic basis of DM in this family.
**Methods:** The proband, a 22-year-old man, had short stature, gray hair, osteoporosis, markedly reduced subcutaneous fat on the extremities, acanthosis nigricans, and developed a myxoid malignant peripheral nerve sheath tumor (MPNST). Detailed family history revealed multiple loops of consanguinity. The proband underwent whole-genome sequencing (WGS), and seven relatives underwent whole-exome sequencing (WES). Runs of homozygosity (ROH) analysis and filtering for rare conserved homozygous variants were performed. RNA sequencing and RT-PCR were used to confirm aberrant splicing.
**Key Results:** The proband and three additional family members (WS 400.15, WS 400.26, WS 400.28) were found to have the homozygous c.561A>G nucleotide variant of the WRN RecQ-like helicase (WRN) gene, consistent with Werner's syndrome. The variant induces a new splicing site on exon 6, resulting in a 98 bp deletion (r.557_654del98) and a truncated protein p.Lys187Trpfs*13. The proband (WS 400.30) presented with DM at age 15, with a random blood glucose of 310 mg/dL and HbA1c of 11.4% (101 mmol/mol). He had a BMI of 15 kg/m², total body fat 22% (63rd percentile), and bone density Z-score of −2.8. He developed a recurrent lipoblastoma-like tumor and eventually MPNST, requiring forearm amputation at age 21. WS 400.15 (maternal uncle, age 52) was diagnosed with DM in his thirties, had bilateral cataracts at age 35, and non-healing ulcers. WS 400.26 (first cousin, age 26) was diagnosed with DM at age 20, had bilateral cataracts at age 14, premature ovarian failure, and blindness due to diabetic retinopathy. WS 400.28 (age 16) had prediabetes (HbA1c 5.7% [39 mmol/mol]) and minimal signs of Werner's syndrome. The c.561A>G variant was previously reported in two other South Asian patients and is considered a founder mutation.
**Clinical Implications:** This report highlights that Werner's syndrome can present with childhood-onset DM, earlier than the typical age of 30–40 years. Clinicians should consider Werner's syndrome in lean patients with early-onset DM, especially with consanguinity, dysmorphic features (short stature, gray hair, cataracts, lipodystrophy), and malignancy. Early surveillance for DM, metabolic derangements, and cancer is recommended. The study underscores the importance of genetic testing in atypical DM presentations.