|Title||Exome sequencing in children with clinically suspected maturity-onset diabetes of the young.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Tosur, 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|
|Date Published||2021 Nov|
|Keywords||Adolescent, 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 Journal||Pediatr Diabetes|
|PubMed Central ID||PMC8530905|
|Grant List||K08 HG008986 / HG / NHGRI NIH HHS / United States |
UM1 HG008898 / HG / NHGRI NIH HHS / United States
Exome sequencing in children with clinically suspected maturity-onset diabetes of the young.
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