Endocrine Abstracts

JOINT3836

Maturity Onset Diabetes of the Young (MODY) is a form of diabetes characterized by autosomal dominant inheritance and early age at diagnosis. Pathogenic variants in HNF1A are associated with MODY3 and most of them are in the coding region. We describe the case of a patient with early-onset diabetes mellitus (DM). Comprehensive genetic testing, including whole-exome-analysis via next generation sequencing (NGS) performed due to multiple affected family members, revealed a heterozygous deep intronic variant in HNF1A, 14 years after DM diagnosis. The index patient (female, 10 years old) was admitted for further evaluation due to random hyperglycemia after a minor trauma. The girl mentioned no symptoms of polyuria, polydipsia or weight loss. At admission she had a HbA1c of 8. 1%, C-peptide was 0. 9 μg/dl and type 1 diabetes associated autoantibodies were negative. An oral glucose tolerance confirmed DM. Regarding her family history, her mother was suffering from DM since the age of 15 years and was treated at first with sulfonylureas and later on with insulin. Her maternal grandmother had kidney cysts and was suffering from DM since the age of 30 years and was treated with oral antidiabetic drugs. Three other family members from the mother´s side were diagnosed with DM at a young age and were treated with sulfonylureas or insulin. None of them had a definite diagnosis regarding DM type. Sequencing of genes associated with MODY types 1-5 (incl. exon/intron boarders ± 20 bp) was performed of the index patient at diagnosis, but revealed no pathologic Results Treatment with sulfonylureas was started due to her strong family history, which was suggestive of monogenic diabetes. A good glycemic control with sulfonylureas was achieved until the age of 16 years, when HbA1c levels increased and treatment with prandial insulin injections was initiated. At the age of 18 years, targeted NGS panel including MODY types 6-14 was, also, negative. At the age of 24 years, whole-exome-sequencing via NGS and re-evaluation of the 14 MODY associated genes including deep intronic regions, revealed the heterozygous intronic variant c. 327-28A>G;p. ? in the HNF1A gene in the index patient, as well as in 4 other affected family members. The variant is absent from gnomAD and clinical databases. Expanding genetic testing, including re-evaluation for deep intronic variants, for young individuals with a strong family history of DM, non-autoimmune DM and negative routine genetic testing, is recommended as it can determine prognosis, treatment and family counseling.