Exome sequencing in children with clinically suspected maturity‐onset diabetes of the young. Issue 7 (19th August 2021)

• Record Type: Journal Article
• Authors: Tosur, Mustafa; Soler‐Alfonso, Claudia; Chan, Katie M.; Khayat, Michael M.; Jhangiani, Shalini N.; Meng, Qingchang; Refaey, Ahmad; Muzny, Donna; Gibbs, Richard A.; Murdock, David R.; Posey, Jennifer E.; Balasubramanyam, Ashok; Redondo, Maria J.; Sabo, Aniko
• Is Part Of: Pediatric diabetes. Volume 22:Issue 7(2021)
• Page Start: 960
• Page End: 968
• Publication Date: 2021-08-19
• Subjects: children -- diabetes -- exome sequencing -- maturity onset diabetes of the young -- MODY; Diabetes in children -- Periodicals; 616.462
• DOI: 10.1111/pedi.13257
• Languages: English
• ISSNs: 1399-543X

Abstract

Abstract: Objective: Commercial gene panels identify pathogenic variants in as low as 27% of patients suspected to have MODY, suggesting the role of yet unidentified pathogenic variants. We sought to identify novel gene variants associated with MODY. Research Design and Methods: We recruited 10 children with a clinical suspicion of MODY but non‐diagnostic commercial MODY gene panels. We performed exome sequencing (ES) in them and their parents. Results: Mean age at diabetes diagnosis was 10 (± 3.8) years. Six were females; 4 were non‐Hispanic white, 5 Hispanic, and 1 Asian. Our variant prioritization analysis identified a pathogenic, de novo variant in INS (c.94G > A, p.Gly32Ser), confirmed by Sanger sequencing, in a proband who was previously diagnosed with "autoantibody‐negative type 1 diabetes (T1D)" at 3 y/o. This rare variant, absent in the general population (gnomAD database), has been reported previously in neonatal diabetes. We also identified a frameshift deletion (c.2650delC, p.Gln884AsnfsTer57) in RFX6 in a child with a previous diagnosis of "autoantibody‐negative T1D" at 12 y/o. The variant was inherited from the mother, who was diagnosed with "thin type 2 diabetes" at 25 y/o. Heterozygous protein‐truncating variants in RFX6 gene have been recently reported in individuals with MODY. Conclusions: We diagnosed two patients with MODY using ES in children initially classified as "T1D". One has a likely pathogenic novel gene variant not previously associated with MODY. We demonstrate the clinical utility of ES in patients with clinical suspicion of MODY.