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 Nov
KeywordsAdolescent, Autoantibodies, Child, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Diagnosis, Differential, Exome Sequencing, Female, Frameshift Mutation, Genetic Variation, Humans, Islets of Langerhans, Male, Mutation, Missense, Pedigree

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.

Alternate JournalPediatr Diabetes
PubMed ID34387403
PubMed Central IDPMC8530905
Grant ListK08 HG008986 / HG / NHGRI NIH HHS / United States
UM1 HG008898 / HG / NHGRI NIH HHS / United States

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