ESPE Abstracts

Objectives: Monogenic diabetes and congenital hyperinsulinism (CHI) and are common disorders of glucose-regulated insulin secretion in childhood, with 13 causative genes known for MODY and 10 causative genes identified for CHI. Genetic testing for monogenic diabetes and CHI is important for patient care. We aimed to delineate genetic and clinical manifestations of monogenic diabetes and CHI diagnosed by targeted-exome sequencing (TES).

Methods: Nine probands and their family members (7 monogenic diabetes and 2 CHI) were included. We conducted TES in 7 clinical CHI and monogenic diabetes families to identify genetic variants in Korea. Variants in the dbSNP135 and TIARA databases for Koreans and the variants with minor allele frequencies >0.5% of the 1000 Genomes database were excluded. We selected only the functional variants and conducted a case-control comparison in the family members. The selected variants were scanned for the previously introduced gene set implicated in glucose metabolism

Results: Among the 5 patients with suspected maturity-onset diabetes of the young (MODY), 2 different MODY were identified in the three patients, and the diagnostic yield was 60%. We identified two novel mutations [C.1088C>T (Ala363Val) and c.1127T>C (Met376Thr)] in HNF4A gene causing MODY1. All the novel HNF4A mutation carriers were successfully transferred from insulin to sulfonylurea. A novel splicing mutation [c.538+8G>C] in PAX9 gene was identified in a family with MODY9. A novel PAX9 mutation carrier had a good clinical response when switched from insulin to diet. We also identified a novel variant in potentially candidate gene implicated in susceptibility to diabetes, albeit thus far not in an autosomal dominant mode of inheritance: NOTCH2. One of two families with neonatal diabetes showed a compound heterozygous mutation, c.2978C>A (Ala993Asp) and C.356C>T (Ala119Val), the latter of which is a novel mutation, in INSR gene who required metformin treatment. The other one showing persistent neonatal diabetes had a missense mutation, c.605G>A (Arg201His), which is a reported mutation, in KCNJ11 gene, who required sulfonylurea such as glibenclamide. In two families with CHI two novel heterozygous mutations was identified: c.4237C>T (Pro1413Ser) and c.905C>T (Thr302Ile), the former of which is associated with diazoxide responsive CHI, the latter is related to diazoxide non-responsive CHI in terms of clinical courses among the patients.

Conclusions: TES can be useful for screening for monogenic diabetes/CHI mutations. Given the extensive genetic and clinical heterogeneity of monogenic diabetes, TES might provide additional diagnostic potential.