The yield of commercial gene panels for MODY has been reported as low as 27% suggesting the role of un-identified gene variants in MODY. We aimed to study novel genetic factors of MODY. We identified 10 probands who had clinical characteristics suggestive of MODY (i.e., positive family history of diabetes, negative islet autoantibodies, and diagnosis of diabetes at <25 y/o) but negative genetic test results on a commercial MODY gene panel. We performed whole-exome sequencing (WES) in probands and their parents. In each trio, we prioritized rare protein-altering variants (stop-gain, frameshift indels, splicing and missense variants) in 70 neonatal diabetes and MODY candidate genes. Mean age at diabetes diagnosis was 10 (± 3.8) years. Six were females; 4 were non-Hispanic white, 5 Hispanic, and 1 Asian. Previously assigned diabetes types were type 1 diabetes (T1D) (n=7), unknown (n=2) and ketosis-prone diabetes (n=1). We found a likely pathogenic, de novo variant in INS gene (c.94G>A, p.Gly32Ser), confirmed by Sanger sequencing, in a proband who was previously diagnosed with T1D at 3 y/o. This very rare variant, absent in the general population (gnomAD database), has been reported previously in multiple individuals with neonatal diabetes. We also identified a frameshift deletion (c.2650delC, p.Gln884AsnfsTer57) in RFX6 gene in a child with a previous diagnosis of T1D at 12 y/o. The variant was inherited from the mother, who was diagnosed with diabetes of unknown etiology at 25 y/o. Heterozygous protein-truncating variants in RFX6 gene have been recently reported in individuals with MODY.
In conclusion, we identified two new MODY cases, with a novel variant not previously associated with MODY in one of them, using WES in children who were initially diagnosed with T1D. Our study demonstrates clinical utility of exome sequencing in atypical cases of diabetes suspected of MODY.
M. Tosur: None. A. Sabo: None. M.M. Khayat: None. S.N. Jhangiani: None. A.K. Refaey: None. D. Muzny: None. R.A. Gibbs: None. A. Balasubramanyam: None. M.J. Redondo: None.
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