HNF4A was first reported in relation to autosomal dominant monogenic diabetes (more specifically in maturity onset diabetes of the young/ MODY) in 1996 (Yamagata et al., 1996 PMID: 8945471). HNF4A is a transcription factor expressed within the liver, kidney, and pancreas of humans (Drewes et al., 1996 PMID: 8622695). HNF4A has been shown to regulate the expression of HNF1A, another transcription factor that is associated with monogenic diabetes, providing a direct correlation between these monogenic diabetes associated genes (Thomas et al., 2001 PMID: 11590126). Numerous variants in HNF4A in relation to the development of monogenic diabetes ( or MODY and hyperinsulinemic hypoglycemia), including missense, frameshift, nonsense and deletions have been reported in humans. There are databases describing HNF4A variants of interest in monogenic diabetes, including: (1) the HNF4A database in LOVD (https://grenada.lumc.nl/LOVD2/diabetes/home.php?select_db=HNF4A); and (2) The Diagnostic Mutation Database (https://secure.dmudb.net/ngrl-rep/Home.do) (Colclough et al., 2013 PMID: 23348805). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This gene-disease relationship has been studied for over 20 years, therefore a significant amount of case-level and segregation data is available, however the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by expression studies, biochemical evidence, and animal models.
HNF4A has been associated with multiple disease entities and/or phenotypes through autosomal dominant germline inheritance, including: (1) Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young (MIM: 616026); (2) MODY, type I (MIM: 125850); (3) Susceptibility to Diabetes mellitus, noninsulin-dependent (MIM: 125853).
The Fanconi renotubular syndrome 4 (FRST4) is associated with a single variant in HNF4A, p.Arg76Trp (aka p.Arg85Trp or Arg63Trp dependent on the transcript used, ref. Flanagan et al., 2010 PMID: 20164212, supplementary table 1) and has been shown to occur in at least 7 different probands (PMIDs: 22802087, 24285859, 25819479, 30005691, 28693455, 28458902, 27245055, 20164212). Renal abnormalities often accompany a diagnosis of MODY. Per the criteria outline by the ClinGen Lumping and Splitting Working Group, FRST4 and MODY1 show the same molecular mechanism and phenotypes consistent with a spectrum of MODY diagnosis, therefore they have been lumped into the disease entity, monogenic diabetes (MONDO:0015967). The susceptibility to diabetes mellitus, non-insulin dependent is not currently curated under this gene-disease relationship and will be evaluated independently.
In summary, HNF4A is DEFINITIVELY associated with autosomal dominant monogenic diabetes. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Monogenic Diabetes Expert Panel on Feb 26, 2019.
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