Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry.

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  • Additional Information
    • Source:
      Publisher: Walter de Gruyter Country of Publication: Germany NLM ID: 9508900 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 2191-0251 (Electronic) Linking ISSN: 0334018X NLM ISO Abbreviation: J Pediatr Endocrinol Metab Subsets: MEDLINE
    • Publication Information:
      Publication: Mar. 2011- : Berlin : Walter de Gruyter
      Original Publication: London : Freund Pub. House, [1995-
    • Subject Terms:
      Mutation*; Biomarkers/*analysis ; Diabetes Mellitus, Type 2/*epidemiology ; Germinal Center Kinases/*genetics ; Hepatocyte Nuclear Factor 1-alpha/*genetics ; Registries/*statistics & numerical data ; Exome Sequencing/*methods; Adult ; Cohort Studies ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/pathology ; Female ; Follow-Up Studies ; Genetic Testing ; Humans ; Male ; New York/epidemiology ; Phenotype ; Prognosis ; Young Adult
    • Abstract:
      Objectives: There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY.
      Methods: We used a tiered testing approach focusing initially on GCK and HNF1A and then expanding to exome sequencing for those individuals without identified mutations in GCK or HNF1A . The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%.
      Results: Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in GCK or HNF1A . Less frequently, mutations were identified in PDX1 , HNF4A , HNF1B , and KCNJ11 . For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation.
      Conclusions: Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.
      (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)
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    • Grant Information:
      P30 DK026687 United States DK NIDDK NIH HHS; R01 DK052431 United States DK NIDDK NIH HHS; T32 DK065522 United States DK NIDDK NIH HHS
    • Contributed Indexing:
      Keywords: MODY; diabetes; genetics in diabetes and obesity; molecular genetics
    • Accession Number:
      0 (Biomarkers)
      0 (Germinal Center Kinases)
      0 (HNF1A protein, human)
      0 (Hepatocyte Nuclear Factor 1-alpha)
      0 (MAP4K2 protein, human)
    • Subject Terms:
      Mason-Type Diabetes
    • Publication Date:
      Date Created: 20210414 Date Completed: 20211123 Latest Revision: 20221207
    • Publication Date:
      20240628
    • Accession Number:
      PMC8970616
    • Accession Number:
      10.1515/jpem-2020-0501
    • Accession Number:
      33852230