Assessment and translation of novel biomarkers for diagnosis of maturity onset diabetes of the young due to HNF1A variants

Juszczak, A

Abstract:: HNF1A-MODY is the most common form of monogenic diabetes, but due to low awareness among clinicians and limited availability of genetic testing in many countries, the majority of cases are misdiagnosed as type 1 or type 2 diabetes. In clinical practice, it is apparent that some young adults with non-autoimmune diabetes share several features of MODY and type 2 diabetes. Hence, I aimed to understand the range of genetic variation in HNF1A in this group and whether we could use biom...
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APA Style

Juszczak, A. (2018). Assessment and translation of novel biomarkers for diagnosis of maturity onset diabetes of the young due to HNF1A variants [PhD thesis]. University of Oxford.

MLA Style

Juszczak, A. Assessment and Translation of Novel Biomarkers for Diagnosis of Maturity Onset Diabetes of the Young Due to HNF1A Variants. 2018. University of Oxford, PhD thesis.

Chicago Style

Juszczak, A. 2018. “Assessment and Translation of Novel Biomarkers for Diagnosis of Maturity Onset Diabetes of the Young Due to HNF1A Variants.” PhD thesis, University of Oxford.
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Authors

+ Juszczak, A More by this author

Institution:: University of Oxford
Division:: MSD
Department:: RDM
Sub department:: OCDEM
Role:: Author

Contributors

+ McCarthy, M

Institution:: University of Oxford
Division:: MSD
Department:: RDM
Sub department:: OCDEM
Role:: Supervisor

+ Owen, K

Institution:: University of Oxford
Division:: MSD
Department:: RDM
Sub department:: OCDEM
Role:: Supervisor

+ Diabetes UK More from this funder

Grant:: 14/0004735

+ OXFORDSHIRE HEALTH SERVICES RESEARCH COMMITTEE More from this funder

Grant:: 1105

DOI:: 10.5287/ora-bdj6ramex
Type of award:: DPhil
Level of award:: Doctoral
Awarding institution:: University of Oxford

Language:: English
UUID:: uuid:e5dcd952-f092-4269-bb9b-35bfd577a031
Deposit date:: 2018-08-20
ARK identifier:: ark:/29072/ora_e5dcd952f0924269bb9b35bfd577a031

Related item:: Maturity onset diabetes of the young due to HNF1A variants in Croatia. Biochem Med (Zagreb). 2018 Jun 15;28(2):020703.
Description:: Maturity onset diabetes of the young due to HNF1A variants (HNF1A-MODY) is the most frequent form of monogenic diabetes in adults. Establishing a genetic diagnosis is important, as treatment differs from common types of diabetes. MODY has not been reported in Croatia before due to limited access to genetic testing. Aims We aimed to describe the characteristics and estimate the prevalence of HNF1A-MODY in Croatia. Methods We recruited 478 C-peptide positive and beta-cell antibody negative patients through the Croatian Diabetes Registry. All participants had HNF1A sequencing and systematic assessment of the variants found was performed. The prevalence of HNF1A-MODY was calculated in the study group and results extrapolated to the population of Croatia. Results Our study identified 13 individuals harbouring rare HNF1A variants in 478 participants, 8 were assigned a diagnosis of HNF1A-MODY. Two individuals were able to discontinue insulin following the diagnosis. We estimated that HNF1A-MODY in Croatia has a prevalence of 66 (95% CI 61 – 72) cases per million of population. Conclusions The estimated prevalence of HNF1A-MODY in Croatia is similar to that reported in other European countries. Finding cases lead to important management changes for patients. This supports the introduction of diagnostic genetic testing in diabetes in Croatia.
Related item:: When to consider a diagnosis of MODY at the presentation of diabetes: aetiology matters for correct management. Br J Gen Pract. 2016 Jun;66(647):e457-9.
Description:: Introduction A GP will often be the first health professional involved in making a diagnosis of diabetes. For adults who do not need immediate insulin treatment, a default diagnosis of type 2 diabetes is the most common outcome, but a small proportion of patients will actually have Maturity-onset diabetes of the young (MODY). MODY is inherited in an autosomal dominant pattern and estimated to account for 1-2% of all diabetes [1]. MODY is most commonly caused by mutations in genes encoding the transcription factors: HNF1A, HNF4A and HNF1B and the glycolytic enzyme glucokinase (GCK) [1]. Making a correct molecular diagnosis is crucial, as this allows optimal treatment and therefore the best long-term outcome. It is estimated that around 80% of MODY patients are misdiagnosed as type 1 or type 2 diabetes [1] and a delay of greater than 10 years from presentation of diabetes to molecular diagnosis is frequently reported [2]. We present two cases where genetic referral for MODY was arranged at presentation of diabetes.
Related item:: Identifying subtypes of monogenic diabetes. Diabetes Management 2014; 4(1): 49-61.
Description:: Monogenic diabetes is estimated at 0.5-1.2% of all diabetes patients and remains underdiagnosed. It consists of variety of subtypes associated with mutations in more than 25 genes. The main groups of monogenic diabetes include maturity onset diabetes of the young (MODY), permanent and transient neonatal diabetes and mitochondrial diabetes. MODY is the most common and is caused most frequently by mutations in transcription factors (HNF1A, HNF4A and HNF1B) or the enzyme glucokinase (GCK). The characteristics of MODY include young-onset non-autoimmune diabetes, usually with a family history, maintenance of endogenous insulin secretion and absence of features of insulin resistance. Correct molecular diagnosis allows personalised treatment and in types sensitive to sulphonylureas often discontinuation of insulin with improved diabetic control.

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Copyright holder:: Juszczak, A

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Assessment and translation of novel biomarkers for diagnosis of maturity onset diabetes of the young due to HNF1A variants

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Assessment and translation of novel biomarkers for diagnosis of maturity onset diabetes of the young due to HNF1A variants

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