Digenic heterozygous HNF1A and HNF4A mutations in two siblings with childhood-onset diabetes

Details

• Alternative Title:
  Pediatr Diabetes
• Personal Author:
  Shankar, Roopa Kanakatti ; Ellard, Sian ; Standiford, Debra ; Pihoker, Catherine ; Gilliam, Lisa K. ; Hattersley, Andrew ; Dolan, Lawrence M.
• Description:
  Monogenic diabetes due to mutations in the transcription factor genes hepatocyte nuclear factor 1A (HNF1A) and HNF4A is characterized by islet cell antibody negative, familial diabetes with residual insulin secretion. We report two sisters with childhood onset diabetes who are both heterozygous for the most common mutation in each of two transcription factors, HNF1A, and HNF4A. The proband was diagnosed with diabetes at 7 yr of age and treated with insulin for 4 yr. Her genetic diagnosis resulted in transition to sulfonylureas for one and a half years before insulin therapy was re-initiated due to declining glycemic control. Her sister was diagnosed with diabetes at 14 yr of age, treated initially with insulin but has been well controlled on oral sulfonylurea therapy for over 2 yr. Both sisters inherited the HNF4A gene mutation R127W from their mother and the HNF1A gene mutation P291fsinsC (c.872dup) from their father. The father was diagnosed with diabetes at 45 yr of age. Their brother is heterozygous for the HNF4A R127W mutation. Both the brother and mother have normal glucose tolerance at the ages of 16 and 46 yr, respectively. Digenic inheritance of HNF1A and HNF4A mutations is very rare and has only been reported in two families where conclusive evidence for the pathogenicity of their mutations was lacking. Follow-up studies in this family co-segregating the two most commonly reported HNF1A/HNF4A mutations will be informative for understanding the effect of digenic inheritance upon phenotypic severity and response to sulfonylurea therapy.
• Subjects:
  Adolescent Article Blood Glucose Child Diabetes Mellitus, Type 2 Female Hepatocyte Nuclear Factor 1-alpha Hepatocyte Nuclear Factor 4 HNF1A HNF4A Humans Male Middle Aged MODY Siblings Sulfonylurea Compounds Youth

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• Source:
  Pediatr Diabetes. 14(7):535-538.
• Pubmed ID:
  23551881
• Pubmed Central ID:
  PMC4090307
• Document Type:
  Journal Article
• Funding:
  00097/PHS HHS/United States ; 1U18DP002709/DP/NCCDPHP CDC HHS/United States ; 1UL1RR026314-01/RR/NCRR NIH HHS/United States ; 200-2010-35171/PHS HHS/United States ; DP-05-069/DP/NCCDPHP CDC HHS/United States ; DP-10-001/DP/NCCDPHP CDC HHS/United States ; M01 RR000037/RR/NCRR NIH HHS/United States ; M01RR00037/RR/NCRR NIH HHS/United States ; M01RR00069/RR/NCRR NIH HHS/United States ; P30 DK57516/DK/NIDDK NIH HHS/United States ; U01 DP000244/DP/NCCDPHP CDC HHS/United States ; U01 DP000245/DP/NCCDPHP CDC HHS/United States ; U01 DP000246/DP/NCCDPHP CDC HHS/United States ; U01 DP000247/DP/NCCDPHP CDC HHS/United States ; U01 DP000248/DP/NCCDPHP CDC HHS/United States ; U01 DP000250/DP/NCCDPHP CDC HHS/United States ; U01 DP000254/DP/NCCDPHP CDC HHS/United States ; U18DP000247-06A1/DP/NCCDPHP CDC HHS/United States ; U18DP002708-01/DP/NCCDPHP CDC HHS/United States ; U18DP002710-01/DP/NCCDPHP CDC HHS/United States ; U18DP002714/DP/NCCDPHP CDC HHS/United States ; U48/CCU419249/PHS HHS/United States ; U48/CCU519239/PHS HHS/United States ; U48/CCU819241-3/PHS HHS/United States ; U48/CCU919219/PHS HHS/United States ; U58/CCU019235-4/PHS HHS/United States ; U58CCU919256/PHS HHS/United States ; UL1 RR025014/RR/NCRR NIH HHS/United States ; UL1 TR000077/TR/NCATS NIH HHS/United States ; UL1 TR000423/TR/NCATS NIH HHS/United States ; UL1RR029882/RR/NCRR NIH HHS/United States
• Volume:
  14
• Issue:
  7
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:8cdbe4cd45bd7533ae87c11ffab34236f6c688222b9d9511ba9c37259ebb5065
• Download URL:
  https://stacks.cdc.gov/view/cdc/30031/cdc_30031_DS1.pdf
• File Type:
  [PDF - 351.37 KB ]