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

Pediatr Diabetes. 2021 Nov;22(7):960-968. doi: 10.1111/pedi.13257. Epub 2021 Aug 19.


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.

Keywords: MODY; children; diabetes; exome sequencing; maturity onset diabetes of the young.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Autoantibodies / blood
  • Child
  • Diabetes Mellitus, Type 1
  • Diabetes Mellitus, Type 2 / genetics*
  • Diagnosis, Differential
  • Exome Sequencing*
  • Female
  • Frameshift Mutation / genetics
  • Genetic Variation
  • Humans
  • Islets of Langerhans / immunology
  • Male
  • Mutation, Missense / genetics
  • Pedigree


  • Autoantibodies