Functional Analyses of HNF1A-MODY Variants Refine the Interpretation of Identified Sequence Variants

Abstract Context While rare variants of the hepatocyte nuclear factor-1 alpha (HNF1A) gene can cause maturity-onset diabetes of the young (HNF1A-MODY), other variants can be risk factors for the development of type 2 diabetes. As has been suggested by the American College of Medical Genetics (ACMG)...

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Published in:The journal of clinical endocrinology and metabolism 2020-04, Vol.105 (4), p.e1377-e1386
Main Authors: Malikova, Jana, Kaci, Alba, Dusatkova, Petra, Aukrust, Ingvild, Torsvik, Janniche, Vesela, Klara, Kankova, Pavla Dvorakova, Njølstad, Pål R, Pruhova, Stepanka, Bjørkhaug, Lise
Format: Article
Language:English
Subjects:
Adult
Bioinformatics
Biomarkers - analysis
Deoxyribonucleic acid
Diabetes
Diabetes mellitus (non-insulin dependent)
Diabetes Mellitus, Type 1 - genetics
Diabetes Mellitus, Type 1 - metabolism
Diabetes Mellitus, Type 1 - pathology
Diabetes Mellitus, Type 2 - genetics
Diabetes Mellitus, Type 2 - metabolism
Diabetes Mellitus, Type 2 - pathology
DNA
Female
Follow-Up Studies
Hepatocyte Nuclear Factor 1-alpha - genetics
Humans
Localization
Male
Mutation
Phenotype
Phenotypes
Prognosis
Reclassification
Risk factors
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Summary:Abstract Context While rare variants of the hepatocyte nuclear factor-1 alpha (HNF1A) gene can cause maturity-onset diabetes of the young (HNF1A-MODY), other variants can be risk factors for the development of type 2 diabetes. As has been suggested by the American College of Medical Genetics (ACMG) guidelines for variant interpretation, functional studies provide strong evidence to classify a variant as pathogenic. Objective We hypothesized that a functional evaluation can improve the interpretation of the HNF1A variants in our Czech MODY Registry. Design, Settings, and Participants We studied 17 HNF1A variants that were identified in 48 individuals (33 female/15 male) from 20 Czech families with diabetes, using bioinformatics in silico tools and functional protein analyses (transactivation, protein expression, DNA binding, and nuclear localization). Results Of the 17 variants, 12 variants (p.Lys120Glu, p.Gln130Glu, p.Arg131Pro, p.Leu139Pro, p.Met154Ile, p.Gln170Ter, p.Glu187SerfsTer40, p.Phe215SerfsTer18, p.Gly253Arg, p.Leu383ArgfsTer3, p.Gly437Val, and p.Thr563HisfsTer85) exhibited significantly reduced transcriptional activity or DNA binding (< 40%) and were classified as (likely) pathogenic, 2/17 variants were (likely) benign and 3/17 remained of uncertain significance. Functional analyses allowed for the reclassification of 10/17 variants (59%). Diabetes treatment was improved in 20/29 (69%) carriers of (likely) pathogenic HNF1A variants. Conclusion Functional evaluation of the HNF1A variants is necessary to better predict the pathogenic effects and to improve the diagnostic interpretation and treatment, particularly in cases where the cosegregation or family history data are not available or where the phenotype is more diverse and overlaps with other types of diabetes.
ISSN:0021-972X
1945-7197
DOI:10.1210/clinem/dgaa051