Exome sequencing in children with clinically suspected maturity-onset diabetes of the young.

TitleExome sequencing in children with clinically suspected maturity-onset diabetes of the young.
Publication TypeJournal Article
Year of Publication2021
AuthorsTosur, M, Soler-Alfonso, C, Chan, KM, Khayat, MM, Jhangiani, SN, Meng, Q, Refaey, A, Muzny, DM, Gibbs, RA, Murdock, DR, Posey, JE, Balasubramanyam, A, Redondo, MJ, Sabo, A
JournalPediatr Diabetes
Date Published2021 Aug 13
ISSN1399-5448
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.

DOI10.1111/pedi.13257
Alternate JournalPediatr Diabetes
PubMed ID34387403
Grant List / / Participant recruitment, exome sequencing and data analysis were supported by Mike Hogg Fund, and NIH/NHGRI grant 1UM1HG008898. Jennifer E. Posey was supported by NIH/NHGRI K08 HG008986 /