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Article

A Comprehensive Analysis of Hungarian MODY Patients—Part II: Glucokinase MODY Is the Most Prevalent Subtype Responsible for about 70% of Confirmed Cases

1
4th Department of Medicine, Jósa András Teaching Hospital, 4400 Nyíregyháza, Hungary
2
Division of Clinical Genetics, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
3
Department of Pediatrics, Jósa András Teaching Hospital, 4400 Nyíregyháza, Hungary
4
1st Department of Pediatrics, Semmelweis University, 1085 Budapest, Hungary
5
Department of Pediatrics, Szent György Hospital of Fejér County, 8000 Székesfehérvár, Hungary
6
Department of Pediatrics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
*
Author to whom correspondence should be addressed.
Submission received: 29 June 2021 / Revised: 20 July 2021 / Accepted: 27 July 2021 / Published: 30 July 2021

Abstract

:
MODY2 is caused by heterozygous inactivating mutations in the glucokinase (GCK) gene that result in persistent, stable and mild fasting hyperglycaemia (5.6–8.0 mmol/L, glycosylated haemoglobin range of 5.6–7.3%). Patients with GCK mutations usually do not require any drug treatment, except during pregnancy. The GCK gene is considered to be responsible for about 20% of all MODY cases, transcription factors for 67% and other genes for 13% of the cases. Based on our findings, GCK and HNF1A mutations together are responsible for about 90% of the cases in Hungary, this ratio being higher than the 70% reported in the literature. More than 70% of these patients have a mutation in the GCK gene, this means that GCK-MODY is the most prevalent form of MODY in Hungary. In the 91 index patients and their 72 family members examined, we have identified a total of 65 different pathogenic (18) and likely pathogenic (47) GCK mutations of which 28 were novel. In two families, de novo GCK mutations were detected. About 30% of the GCK-MODY patients examined were receiving unnecessary OAD or insulin therapy at the time of requesting their genetic testing, therefore the importance of having a molecular genetic diagnosis can lead to a major improvement in their quality of life.

1. Introduction

1.1. GCK-MODY (MODY2)

MODY2 is caused by heterozygous inactivating mutations in the glucokinase (GCK) gene encoding a key regulator glycolytic enzyme of the hexokinase family [1]. It has two tissue-specific promoters and a different exon 1, the upstream promoter being functional in the pancreas (exon 1a) and brain, while the downstream one only in the liver (exons 1b and 1c), resulting in different isoforms of the GCK gene [2,3].
GCK has an important role in carbohydrate metabolism. It is responsible for the catalysis of the first reaction of the glycolytic pathway, the glucose phosphorylation [1]. GCK acts as a glucose sensor of the pancreatic beta-cells [1], therefore it is critical in the process of the regulation of insulin secretion and release.
In the case of GCK-MODY, a mildly elevated glucose level is caused by heterozygous loss-of-function mutations in the GCK gene. Any of the 10 exons and promoter of the pancreatic isoform of the GCK gene might be affected as no mutational hotspots have been identified. The mutations might affect enzyme kinetics or protein folding [4,5]. To date, almost 800 disease-causing small scale GCK mutations have been reported in the professional version of the HGMD (Human Gene Mutation Database, version 2021.1) associated with the MODY phenotype, the majority of them being missense alterations resulting in abnormal structure and/or function of the mutant protein, often affecting its kinetic parameters.
GCK gene mutations result in abnormal glucose sensing, raising the threshold of glucose-mediated insulin secretion. As a consequence, stable and mild fasting hyperglycaemia (5.6–8.0 mmol/L, glycosylated haemoglobin range of 5.6–7.3%) persists that does not deteriorate with age and is not associated with an increased risk of complications [6,7]. The clinical manifestation of GCK-MODY is generally nonprogressive, usually asymptomatic in childhood. The elevated glucose level is present from birth, therefore it is mostly detected incidentally [8,9]. Performing an oral glucose tolerance test (OGTT) can help to distinguish GCK-MODY patients from other types of MODY as in the case of GCK-MODY, patients generally have a small (<3.5 mmol/L) 2 h glucose increment [10].
Patients with GCK mutations usually do not require any drug treatment (except during pregnancy or in critical clinical situations), however, they often receive unnecessary insulin therapy or oral antidiabetic drug treatment [9]. Good glycaemic control can usually be achieved with only diet and exercise [11].

1.2. MODY Prevalence

The estimated MODY prevalence is around 1–5% of all diabetes mellitus cases, but it varies depending on the population studied [12,13]. The GCK gene is considered to be responsible for about 20% of all MODY cases, transcription factors for 67% and other genes for 13% of the cases [14]. GCK and HNF1A genes together are responsible for about 70% of all known MODY cases, the ratio of the two genes widely varying between countries [15]. For example in the United Kingdom, the prevalence of GCK-MODY is reported to be 32% [6,16], and 63% in the case of HNF1A-MODY [17]. The Norwegian MODY Registry reports a distribution of 53% HNF1A-MODY, 30% GCK-MODY, 7.5% HNF4A-MODY and 5.6% HNF1B-MODY [18]. A Polish study reports GCK-MODY to be the most prevalent with 83% [19] while the American SEARCH study reports HNF1A-MODY as the most prevalent form with roughly 60%, GCK-MODY being in the second position with 30% [20].

2. Materials and Methods

As this paper is Part II of two accompanying publications in the Journal, the patients and methods presented in this section are the same as the ones described in Part I of this article. The genes tested and genetic methods used during the study are presented in the Supplementary file (Part I of these articles).

2.1. Patients

A total of 450 unrelated index patients with suspected MODY diagnosis and their 202 family members have been referred to our laboratory for genetic testing from all around Hungary. All participants or their guardians have given informed consent to genetic testing according to national regulations.

2.2. Methods

Genomic DNA was isolated from peripheral blood leukocytes using the QIAamp Blood Mini kit (Qiagen GmbH, Hilden, Germany).
In the case of 102 index patients, Sanger sequencing of the GCK, HNF1A or HNF4A genes was performed using the BigDye Terminator v3.1 Cycle Sequencing kit (Applied Biosystems, Foster City, CA, USA) according to the manufacturer’s protocol.
Bidirectional pyrosequencing with a minimum coverage of 40× was performed on Roche GS Junior 454 pyrosequencing system (Roche 454 Life Sciences, Branford, CT, USA) in the case of 33 index patients.
The 311 index patient samples were sequenced on Illumina Miseq or NextSeq 550 (Illumina, San Diego, CA, USA) sequencer systems in 2 × 150 cycle (or 2 × 250 cycle in the case of the MODY MASTR kit) paired-end mode. Three different library preparation methods were used before sequencing. The MODY MASTR kit (Multiplicom, Niel, Belgium) was used to examine 7 genes in the case of 76 index patients. A custom-made and enrichment-based DNA library preparation kit (Qiagen, GmbH, Hilden, Germany) containing 17 genes was used in the case of 164 index patients, and another custom-designed gene panel (Twist Bioscience, South San Francisco, CA, USA) was used, examining 18 genes in the case of 69, and 20 genes in the case of 6 index patients. (Supplementary Table S1, see Part I) In the case of Illumina sequenced data, data analysis was performed using the NextGene software (SoftGenetics, State College, PA, USA).
MLPA (multiplex ligation-dependent probe amplification) was performed in the case of 32 index patients (as a single test in the case of 4 index patients and in addition to one of the above-mentioned methods in the case of 28 index patients) using SALSA MLPA Probemix P241 MODY Mix 1 and/or SALSA MLPA Probemix P357 MODY Mix 2 (MRC Holland, Amsterdam, Netherlands) according to the manufacturer’s protocol.
The testing method(s) used in the case of every index patient is described in the Supplementary Table S2 (Part I of these articles).
Cascade testing was performed in 202 family members usually by targeted Sanger sequencing of the respective exon of the MODY-causing gene in which their relative had a possibly pathogenic mutation.

2.3. Variant Confirmation

All variants obtained with next-generation sequencing that were suspected to be disease-causing were validated by Sanger sequencing. Furthermore, when the amplicon’s minimum coverage was <40× in the NGS data, the respective exons were also sequenced using the Sanger method.

2.4. Variant Filtering and Interpretation

All detected variants having a MAF > 0.01 (minor allele frequency) in the gnomAD population database were filtered. The remaining variants were classified according to the ACMG standards and guidelines [21,22]. A web-based interpretation tool, Franklin (Genoox) [23] was used to assist the classification. HGMD Professional and ClinVar databases were also used in variant interpretation.

2.5. Clinical Data Collection

Clinical data of patients and family members having a ‘pathogenic’ (‘P’) or ‘likely pathogenic’ (‘LP’) mutation in one of the MODY-causing genes was collected from their application form sent and filled out by their clinician at the time of requesting the genetic testing. The MODY probability calculator (https://www.diabetesgenes.org/, accessed on 20 March 2021) was used to calculate the probability of the patient having MODY when all the information required was available and the patient was under the age of 35, as the calculator cannot be used in case of patients older than that.

3. Results

GCK Mutations
From the 450 index patients examined, 132 tested positive for a pathogenic or likely pathogenic classified variant in one of the MODY-causing genes with a total of 89 mutations. GCK and HNF1A mutations together were responsible for about 90% of the cases, this ratio being higher in Hungary than the 70% reported in the literature [15]. More than 70% (65/89) of the mutations among the index patients were found in the GCK gene (Table 1). With targeted cascade testing of family members, we identified an additional 95 positive cases, resulting in a total of 227 patients with a molecular genetic diagnosis of MODY. More than 70% of these patients have a mutation in the GCK gene, which means that GCK-MODY is the most prevalent form of MODY in Hungary.
In the 91 index patients and their 72 family members, we have identified a total of 65 different pathogenic (18) and likely pathogenic (47) GCK mutations, summarized in Table 2 and Figure 1. Every mutation detected was in heterozygous form. Eighteen mutations were found in more than one apparently unrelated families, the most frequent ones being p.Arg36Trp (5 families), p.Gly261Arg (G > A 5 families and G > C 1 family) and p.Ser340Asn (5 families). Of the detected mutations, 40% (28/65) are novel, while 60% (37/65) have been previously described in the literature. Almost 85% (55/65) of the detected GCK mutations were missense mutations resulting in an amino acid change. In addition, four such mutations were found at exon/intron boundaries of the coding sequence, possibly disrupting exon splicing as well (Table 3).
In the case of two families (F101, F173), the p.Ala188Thr and p.Val226Glu mutations were both detected and co-segregated in the proband and her parent, suggesting a cis position.
Table 4 presents the clinical data of the index patients and their family members. Obesity is not characteristic of these patients, only about 10% of them have their BMI out of the range considered healthy. The age of diagnosis differs widely among the patients, and they have generally received their molecular genetic diagnosis of MODY several years after their diagnosis of diabetes. We had information regarding their treatment in 125 cases. Almost half of the patients examined do not receive any treatment or control their blood sugar levels only by maintaining a healthy diet, which is in accordance with the literature. However, around 10% of these patients receive unnecessary insulin treatment and another 16% are on some oral antidiabetic drug, also unnecessary (Table 5). Their HbA1c levels are generally around 7.0% or lower.
The detected GCK mutation was shown to be de novo in two cases (Table 4, F041 and F375).
We had enough information to use the MODY calculator in about half of the patients. In the case of about three-quarters of these patients (62/81), the calculator showed a 75.5% probability of the patient having MODY, this was the highest probability we could get using the calculator.

4. Discussion

Two hundred and twenty-seven patients were diagnosed with MODY in our examined cohort from all over Hungary in about 10 years with a 70% mutation rate in the GCK gene, meaning that the most prevalent form of monogenic diabetes in Hungary is the GCK-MODY.
Although GCK-MODY patients generally do not need any treatment, around 30% of the patients examined were receiving an unnecessary OAD or insulin therapy. We would like to emphasize once again the importance of having a proper molecular genetic diagnosis, as this can lead to a major improvement in the patients’ quality of life by stopping their drug treatment.
The majority of the examined patients had an HbA1c level of 7.0% or lower, this being in accordance with the mildly elevated level reported in the literature and in contrast with the HNF1A patients we examined, where about 60% of the patients had a value of 7.0% or above.
As two families had de novo GCK mutations, one criterion of MODY about the transgenerational occurrence of the disease should be treated with caution—the lack of apparent inheritance pattern does not exclude the possibility of having a MODY.
The effect of the pathogenic and likely pathogenic mutations on the kinetics of the glucokinase enzyme is still not precisely known in many cases, therefore we plan to further investigate this question in the future.

Supplementary Materials

The following are available online at https://0-www-mdpi-com.brum.beds.ac.uk/article/10.3390/life11080771/s1, Table S1. The list of genes examined with the different library preparation kits; Table S2. Methods used for testing the index patients; Table S3. Clinical data of patients with HNF1A mutation; Table S4. Clinical data of patients having a mutation in other MODY-causing genes.

Author Contributions

Conceptualization of the study, I.B. and Z.G.; methodology, Z.S. and L.M.; clinical data analysis, Z.G., I.K., A.L., P.T.-H., O.B., E.F., and Z.K.; writing—original draft preparation, Z.S.; writing—review and editing, all authors; funding acquisition, Z.G., I.B. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by OTKA K109076 and Ministry of National Economy, Hungary GINOP-2.3.2-15-2016-00039 (to I.B.).

Institutional Review Board Statement

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Patients gave informed written consent. The laboratory is approved by the National Public Health and Medical Officer Service (approval number: 094025024).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

The data presented in this study are available on request from the corresponding author.

Conflicts of Interest

The authors declare no conflict of interest. Part of the data of this paper is being presented on the 60th National Congress of the Hungarian Society of Laboratory Medicine Online Congress, 26–28 August 2021.

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Figure 1. GCK mutations detected in the index patients. Novel mutations are shown in colour.
Figure 1. GCK mutations detected in the index patients. Novel mutations are shown in colour.
Life 11 00771 g001
Table 1. Number of patients harbouring a pathogenic/likely pathogenic mutation in one of the MODY-causing genes.
Table 1. Number of patients harbouring a pathogenic/likely pathogenic mutation in one of the MODY-causing genes.
GeneNo. of Index Patients with
‘P’/’LP’ Mutations
No. of Index Patients and Their Family Members with
‘P’/’LP’ Mutations
GCK91 (68.9%)163 (71.8%)
HNF1A30 (22.7%)48 (21.1%)
other MODY-causing gene 111 (8.3%)16 (7.0%)
Total132 (100.0%)227 (100.0%)
1 ABCC8, HNF1B, HNF4A, INS, KCNJ11. P: pathogenic; LP: likely pathogenic.
Table 2. Pathogenic (18) and likely pathogenic (47) mutations in the GCK gene.
Table 2. Pathogenic (18) and likely pathogenic (47) mutations in the GCK gene.
Nucleotide ChangeProtein ChangeExon/IntronFunctionACMGACMG EvidenceClinVargnomAD Alleles (MAF)Pr/FMFamily IDNovel/KnownReference
c.98T > Cp.Val33Alaexon 2MissensePathogenicPM1 (2); PM2 (2); PM5 (1); PP2 (1); PP3 (1); PP5 (3)Pathogenic (1)N/A2/0F306, F454known[24]
c.106C > Tp.Arg36Trpexon 2MissensePathogenicPM1 (2); PM2 (2); PM5 (1); PP1 (2); PP2 (1); PP3 (1); PP5 (3)Pathogenic/
Likely pathogenic (4)
4 (0.00001414)5/4F028, F105, F310, F433, F434known[25]
c.115_117delAAGp.Lys39delexon 2In-FramePathogenicPM1 (2); PM2 (2); PM4 (2); PP1 (3)N/AN/A1/2F044known[26]
c.130G > Ap.Gly44Serexon 2MissensePathogenicPM1 (2); PM2 (2); PM5 (1); PP1 (3); PP2 (1); PP3 (1); PP5 (3)Pathogenic (1)N/A1/3F133known[27]
c.171G > Tp.Met57Ileexon 2MissensePathogenicPM1 (2); PM2 (2); PP2 (1); PP3 (1); PP5 (3); PS1 (1)Pathogenic (1)N/A1/0F463novel
c.208G > Ap.Glu70Lysexon 2Missense/SplicingLikely pathogenicPM1 (2); PM2 (2); PP2 (1); PP3 (1); PP5 (1)N/AN/A1/0F389known[28]
c.209-1G > ASpliceintron 2SplicingLikely pathogenicPM2 (2); PVS1 (4)N/A1 (0.00003186)1/0F499novel
c.215G > Cp.Gly72Alaexon 3MissenseLikely pathogenicPM1 (2); PM2 (2); PM5 (2); PP1 (2); PP2 (1); PP3 (1)N/AN/A2/3F069, F274novel
c.232G > Cp.Asp78Hisexon 3MissenseLikely pathogenicPM1 (2); PM2 (2); PP2 (1); PP3 (1)N/AN/A1/3F006known[29]
c.244A > Cp.Thr82Proexon 3MissenseLikely pathogenicPM1 (2); PM2 (2); PM5 (1); PP2 (1); PP3 (1)N/AN/A1/1F472known[30]
c.266T > Gp.Val89Glyexon 3MissenseLikely pathogenicPM1 (2); PM2 (2); PP2 (1); PP3 (1)N/AN/A1/1F213novel
c.371A > Tp.Asp124Valexon 4MissenseLikely pathogenicPM1 (2); PM2 (2); PM5 (1); PP1 (1); PP2 (1); PP3 (1); PP5 (2)Likely pathogenic (1)N/A1/1F083novel
c.425A > Cp.Lys142Threxon 4MissenseLikely pathogenicPM1 (2); PM2 (2); PP2 (1); PP3 (1)N/AN/A1/0F250novel
c.437T > Gp.Leu146Argexon 4MissenseLikely pathogenicPM1 (2); PM2 (2); PP2 (1); PP3 (1)N/AN/A1/0F018known[31]
c.457C > Tp.Pro153Serexon 4MissenseLikely pathogenicPM1 (2); PM2 (2); PP1 (1); PP2 (1); PP3 (1)Uncertain
significance (2)
N/A1/1F103known[32]
c.460G > Ap.Val154Metexon 4MissenseLikely pathogenicPM1 (2); PM2 (2); PP1 (2); PP2 (1); PP3 (1)N/AN/A1/1F381novel
c.494T > Cp.Leu165Proexon 5MissenseLikely pathogenicPM1 (2); PM2 (2); PP2 (1); PP3 (1)N/AN/A2/0F092, F291known[33]
c.501G > Cp.Trp167Cysexon 5MissenseLikely pathogenicPM1 (2); PM2 (2); PP2 (1); PP3 (1)N/AN/A1/0F349novel
c.518C > Ap.Ala173Aspexon 5MissenseLikely pathogenicPM1 (2); PM2 (2); PP2 (1); PP3 (1)N/AN/A1/0F002novel
c.562G > Ap.Ala188Threxon 5MissensePathogenicPM1 (2); PM2 (2); PM5 (1); PP1 (2); PP2 (1); PP3 (1); PP5 (3)Pathogenic (2)1 (0.000003982)2/2F101, F173known[34]
c.572G > Cp.Arg191Proexon 5MissenseLikely pathogenicPM1 (2); PM2 (2); PM5 (2); PP2 (1); PP3 (1)N/AN/A1/0F374novel
c.599T > Cp.Val200Alaexon 6MissenseLikely pathogenicPM1 (2); PM2 (2); PP2 (1); PP3 (1)N/AN/A1/0F094known[10]
c.617C > Tp.Thr206Metexon 6MissenseLikely pathogenicPM1 (2); PM2 (2); PM5 (2); PP1 (2); PP2 (1); PP3 (1); PP5 (1)N/A1 (0.000003977)2/2F031, F116known[35]
c.620T > Cp.Val207Alaexon 6MissenseLikely pathogenicPM1 (2); PM2 (2); PP2 (1); PP3 (1)N/AN/A1/0F316novel
c.622G > Tp.Ala208Serexon 6MissenseLikely pathogenicPM1 (2); PM2 (2); PM5 (1); PP2 (1); PP3 (1)N/AN/A1/0F205novel
c.623C > Tp.Ala208Valexon 6MissensePathogenicPM1 (2); PM2 (2); PM5 (1); PP1 (3); PP2 (1); PP3 (1)Uncertain
significance (1)
1 (0.000003977)1/2F227known[36]
c.626C > Tp.Thr209Metexon 6MissensePathogenicPM1 (2); PM2 (2); PP1 (2); PP2 (1); PP3 (1); PP5 (3)Pathogenic (1)N/A3/1F041, F042, F153known[25]
c.649G > Ap.Asp217Asnexon 6MissenseLikely pathogenicBS4 (1); PM1 (2); PM2 (2); PP2 (1); PP3 (1)Uncertain
significance (4)
11/0F150known[37]
c.660C > Ap.Cys220*exon 6NonsenseLikely pathogenicPM2 (2); PVS1 (4)N/AN/A1/0F165known[38]
c.668G > Ap.Gly223Aspexon 6MissenseLikely pathogenicPM1 (2); PM2 (2); PM5 (2); PP2 (1); PP3 (1)N/AN/A1/2F411novel
c.677T > Ap.Val226Gluexon 6MissenseLikely pathogenicPM1 (2); PM2 (2); PM5 (2); PP1 (2); PP2 (1); PP3 (1)N/AN/A2/2F101, F173known[39]
c.683C > Tp.Thr228Metexon 7MissensePathogenicPM1 (2); PM2 (2); PM5 (1); PP2 (1); PP3 (1); PP5 (3)Pathogenic (5)1 (0.000003999)1/0F065known[40]
c.702C > Ap.Tyr234*exon 7NonsensePathogenicPM2 (2); PP1 (2); PVS1 (4)N/AN/A2/2F011, F244known[41]
c.709_711delGAGp.Glu237delexon 7In-frameLikely pathogenicPM1 (2); PM2 (2); PM4 (2); PP1 (2)N/AN/A2/1F070, F246novel
c.724G > Tp.Glu242*exon 7NonsensePathogenicPM2 (2); PP1 (3); PVS1 (4)N/AN/A1/3F382novel
c.730G > Ap.Val244Metexon 7MissenseLikely pathogenicPM1 (2); PM2 (2); PP2 (1); PP3 (1); PP5 (1)Conflicting
(1 LP, 1 VUS)
N/A1/0F400novel
c.742G > Ap.Glu248Lysexon 7MissenseLikely pathogenicPM1 (2); PM2 (2); PP2 (1); PP3 (1); PP5 (1)N/A1 (0.000003982)1/0F219known[42]
c.752T > Gp.Met251Argexon 7MissensePathogenicPM1 (2); PM2 (2); PM5 (1); PP1 (3); PP2 (1); PP3 (1)N/AN/A1/4F145known[10]
c.778T > Gp.Phe260Valexon 7MissenseLikely pathogenicPM1 (2); PM2 (2); PM5 (1); PP2 (1); PP3 (1)N/AN/A2/2F408, F455 known[43]
c.781G > Ap.Gly261Argexon 7MissensePathogenicPM1 (2); PM2 (2); PP1 (1); PP2 (1); PP3 (1); PP5 (3); PS1 (3)Pathogenic (4)1
(0.000003983)
4/1F126, F191, F202, F272known[40]
c.781G > Cp.Gly261Argexon 7MissensePathogenicPM1 (2); PM2 (2); PP2 (1); PP3 (1); PP5 (3); PS1 (3)Pathogenic (1)N/A1/0F108known[44]
c.790G > Ap.Gly264Serexon 7MissenseLikely pathogenicPM1 (2); PM2 (2); PP2 (1); PP3 (1); PP5 (1)Pathogenic (1)N/A2/0F080, F216known[35]
c.793G > Tp.Glu265*exon 7NonsensePathogenicPM2 (2); PP1 (1); PP5 (3); PVS1 (4)Pathogenic (2)N/A1/1F035known[45]
c.822C > Ap.Asp274Gluexon 7MissenseLikely pathogenicPM1 (2); PM2 (2); PP2 (1); PP3 (1)N/A1 (0.000003992)1/0F280novel
c.824G > Cp.Arg275Proexon 7MissenseLikely pathogenicPM1 (2); PM2 (2); PM5 (1); PP2 (1); PP3 (1)N/AN/A1/0F107novel
c.863T > Cp.Leu288Proexon 7Missense/splicingLikely pathogenicPM1 (2); PM2 (2); PP2 (1); PP3 (1)N/AN/A1/1F403novel
c.869A > Gp.Glu290Glyexon 8MissenseLikely pathogenicPM1 (2); PM2 (2); PP1 (2); PP2 (1); PP3 (1)N/AN/A1/0F375novel
c.872A > Tp.Lys291Metexon 8MissensePathogenicPM1 (2); PM2 (2); PM5 (1); PP1 (3); PP2 (1); PP3 (1)N/AN/A2/6F043, F046novel
c.884G > Ap.Gly295Aspexon 8MissenseLikely pathogenicPM1 (2); PM2 (2); PP1 (1); PP2 (1); PP3 (1)N/AN/A1/1F038known[39]
c.886A > Cp.Lys296Glnexon 8MissenseLikely pathogenicPM1 (2); PM2 (2); PP2 (1); PP3 (1)N/A2 (0.000008008)1/0F296novel
c.908G > Ap.Arg303Glnexon 8MissenseLikely pathogenicPM1 (2); PM2 (2); PM5 (1); PP2 (1); PP3 (1); PP5 (2)Likely pathogenic (1)N/A1/1F167known[46]
c.952G > Ap.Gly318Argexon 8MissensePathogenicPM1 (2); PM2 (2); PM5 (1); PP1 (3); PP2 (1); PP3 (1); PP5 (3)Pathogenic (1)N/A3/5F016, F209, F353known[47]
c.982delGp.Gly328Glufs*25exon 8FrameshiftPathogenicPM2 (2); PP1 (3); PVS1 (4)N/AN/A2/5F085, F162novel
c.989T > Cp.Phe330Serexon 8MissenseLikely pathogenicPM1 (2); PM2 (2); PP1 (1); PP2 (1); PP3 (1)Uncertain
significance (1)
N/A1/1F122known[48]
c.1019G > Ap.Ser340Asnexon 8Missense/
splicing
Likely pathogenicPM1 (2); PM2 (2); PM5 (1); PP1 (2); PP2 (1); PP3 (1)N/AN/A5/4F027, F062, F163, F187, F197known[32]
c.1019G > Cp.Ser340Threxon 8Missense/
splicing
Likely pathogenicPM1 (2); PM2 (2); PM5 (1); PP1 (1); PP2 (1); PP3 (1)N/AN/A1/1F435known[49]
c.1019 + 1G > TSpliceintron 8SplicingLikely pathogenicPM2 (2); PVS1 (3)N/AN/A1/0F131known[50]
c.1130G > Cp.Arg377Proexon 9MissenseLikely pathogenicPM1 (2); PM2 (2); PM5 (2); PP2 (1); PP3 (1)N/AN/A1/0F482novel
c.1139A > Cp.His380Proexon 9MissenseLikely pathogenicPM1 (2); PM2 (2); PP1 (1); PP2 (1); PP3 (1)N/AN/A1/1F200novel
c.1186_1193delAGCCGCAGp.Ser396Argfs*60exon 9FrameshiftLikely pathogenicPM2 (2); PVS1 (4)N/AN/A1/0F314novel
c.1225G > Cp.Asp409Hisexon 9MissenseLikely pathogenicPM1 (2); PM2 (2); PP1 (1); PP2 (1); PP3 (1)N/AN/A1/1F113novel
c.1268T > Cp.Phe423Serexon 10MissenseLikely pathogenicPM1 (2); PM2 (2); PM5 (1); PP2 (1); PP3 (1)Uncertain
significance (1)
N/A1/0F275known[51]
c.1340G > Ap.Arg447Glnexon 10MissenseLikely pathogenicPM1 (2); PM2 (2); PM5 (1); PP1 (2); PP2 (1); PP3 (1); PP5 (2)Likely pathogenic (1)N/A2/2F201, F373known[29,42]
c.1340G > Cp.Arg447Proexon 10MissenseLikely pathogenicPM1 (2); PM2 (2); PM5 (1); PP2 (1); PP3 (1)Uncertain
significance (1)
N/A1/0F273known[52]
c.1355T > Gp.Val452Glyexon 10MissenseLikely pathogenicPM1 (2); PM2 (2); PP2 (1); PP3 (1)N/AN/A1/0F263novel
GCK reference sequence: NM_000162.5, novel mutations are shown in bold. ACMG: shows the classification of the mutation based on the ACMG guidelines; ACMG evidence: the criteria and their strength used for the ACMG classification, as follows: (1)—supporting, (2)—moderate, (3)—strong, (4)—very strong, (5)—stand-alone; ClinVar: the classification of the mutation according to ClinVar, with the number of submissions in brackets; gnomAD MAF: minor allele frequency of the mutation in the gnomAD database; Pr/FM: number of probands/their family members the mutation was found in; family ID: identification of the families the mutation was found in.
Table 3. GCK mutations distributed by the amino acid consequence.
Table 3. GCK mutations distributed by the amino acid consequence.
ConsequenceNo. of Mutations
Missense51 (78.5%)
Missense and/or splicing4 (6.2%)
Splicing21 (3.1%)
Nonsense4 (6.2%)
Frameshift2 (3.1%)
In-frame2 (3.1%)
Table 4. Clinical data of patients with GCK mutation.
Table 4. Clinical data of patients with GCK mutation.
Family
ID
Sample IDAge at Diagnosis of DiabetesAge at Receiving Genetic DgBMI *ObesityComplicationsTherapy BEFORE Genetic DiagnosisFPG (0′) (mmol/L)PPG (120′) (mmol/L)HbA1c % (mmol/mol)MODY
Calculator (%)
Family Screening
F002P002324726.2nononeOAD—metformin7.3N/A6.3 (45.4)15.1no family members tested
F006P01531N/A23nononeinsulin6.819.06.7 (49.7)12.6multiple generations affected
F006P01646N/A33yesIHD, PADinsulin7.012.08.2 (66.1)N/Amultiple generations affected
F006P0173415.6nononediet6.09.0N/AN/Amultiple generations affected
F006P018no diabetes1N/AN/AN/AN/AN/AN/AN/AN/Amultiple generations affected
F011P028172719.8nononeOAD—acarbose7.06.06.2 (44.3)75.5multiple generations affected
F011P029425324.7nononeOAD—
sulphonylurea
9.25.26.5 (47.5)N/Amultiple generations affected
F011P0302315.4nononediet6.7N/AN/AN/Amultiple generations affected
F016P037childhood3025nononeOAD—metformin5.86.26.6 (48.6)N/Amultiple generations affected
F016P038no diabetes3N/AN/AnoneN/AN/AN/AN/AN/Amultiple generations affected
F016P0401533N/AN/Anonediet7.6N/AN/AN/Amultiple generations affected
F016P041N/A5N/AN/Anonediet5.88.16.1 (43.2)N/Amultiple generations affected
F016P042N/A55N/AN/AN/AN/AN/AN/AN/AN/Amultiple generations affected
F016P044N/A14N/AN/AN/AN/AN/AN/AN/AN/Amultiple generations affected
F018P0471014N/AN/Anonediet6.5N/A6.3 (45.4)N/Ano family members tested
F027P063N/A25N/AN/Anonediet6.18.86.2 (44.3)N/Ano family members tested
F028P064101219.4nononeN/A7.18.5N/AN/Amultiple generations affected
F028P065N/A1123.2nononeOAD—metformin6.27.16.5 (47.5)N/Amultiple generations affected
F028P066N/A41N/AN/Anonenone6.76.7N/AN/Amultiple generations affected
F031P06981116.2nononeOAD—metformin7.67.96.7 (49.7)75.5multiple generations affected
F031P0702740N/AN/AN/AdietN/AN/AN/AN/Amultiple generations affected
F035P07481119.1nononediet6.015.26.2 (43.2)75.5multiple generations affected
F035P075264023.2noN/AOAD—metforminN/AN/AN/AN/Amultiple generations affected
F038P078N/A36N/AN/AN/AN/AN/AN/AN/AN/Amultiple generations affected
F038P07971215.2nononenone6.58.6N/AN/Amultiple generations affected
F041P08281014.31nononediet8.111.66.2 (44.3)75.5de novo
F042P0854715.7nononediet6.08.56.4 (46.4)75.5siblings positive, parents not tested
F042P08611N/AN/AN/AN/AN/AN/A4.8 (29.0)N/Asiblings positive, parents not tested
F043P088203421.5nononediet7.9N/A6.4 (46.4)75.5no family members tested
F044P089141724nononeinsulin5.1N/A6.8 (50.8)49.4multiple generations affected
F044P090N/A4829.5norenal cystsN/A6.9N/A6.7 (49.7)N/Amultiple generations affected
F044P091466921noTIA, glaucoma, osteoporosisOAD—metformin5.1N/A6.6 (48.6)N/Amultiple generations affected
F046P104184522.0nononenoneN/AN/A5.5 (36.6)75.5multiple generations affected
F046P105131823.7nononeinsulin7.311.26.7 (49.7)49.4multiple generations affected
F046P106142418.5nononeinsulin6.09.56.2 (44.3)75.5multiple generations affected
F046P108152019.4nononeinsulin7.78.77.0 (53.0)8.2multiple generations affected
F046P113N/A1N/AN/AN/AN/AN/AN/AN/AN/Amultiple generations affected
F046P738N/A315.5nononenone5.7N/A6.0 (42.1)N/Amultiple generations affected
F046P739N/A615.7nononenone5.8N/A6.1 (43.2)N/Amultiple generations affected
F062P12833N/AN/Anonenone6.05.4N/AN/Amultiple generations affected
F062P129no diabetes1N/AN/AN/AN/AN/AN/AN/AN/Amultiple generations affected
F062P130no diabetesN/AN/AN/AN/AN/AN/AN/AN/AN/Amultiple generations affected
F065P133112330yesN/AinsulinN/AN/A6.6 (48.6)12.6no family members tested
F069P141161818.7nononeOAD—metformin6.8N/A5.7 (38.8)75.5multiple generations affected
F069P142N/A51N/AN/AN/AN/A6.9N/A6.4 (46.4)N/Amultiple generations affected
F069P143N/A64N/AN/AN/AN/A7.1N/A6.4 (46.4)N/Amultiple generations affected
F070P144N/A2318.7noligament tearOAD—metformin7.1N/A6.0 (42.1)N/Ano family members tested
F080P138N/A8N/AN/AN/AN/A5–7N/AN/AN/Ano family members tested
F083P157N/A24N/AN/APCOSnone6.97.9N/AN/Amultiple generations affected
F083P1581550N/AN/AN/AOAD—metformin7.78N/A6.3 (45.4)N/Amultiple generations affected
F085P160161820.1nononediet7.17.96.8 (50.8)75.5multiple generations affected
F085P161153217.8nononediet6N/A6.1 (43.2)75.5multiple generations affected
F085P16222N/AN/Agranuloma annularediet6.1N/A6.1 (43.2)N/Amultiple generations affected
F092P170N/A15N/AN/Anonediet6.69.46.5 (47.5)N/Ano family members tested
F094P172101519.4nononediet7.29.66.4 (46.4)75.5parents not tested
F101P1926713.4nononenone6.010.06.0 (42.1)75.5multiple generations affected
F101P193no diabetes46normalnoN/AN/AN/AN/AN/AN/Amultiple generations affected
F103P1965617nononediet6.25.86.3 (45.4)75.5multiple generations affected
F103P197364224nononeinsulin6.913.66.0 (42.1)N/Amultiple generations affected
F105P19991420.9noN/Adiet7.3N/AN/AN/Amultiple generations affected
F105P200253730.1yesnonenoneN/AN/AN/AN/Amultiple generations affected
F105P202N/A615.1nononenoneN/AN/AN/AN/Amultiple generations affected
F107P204161719nononediet7.98.87.0 (53.0)75.5no family members tested
F108P205213015.1nononeinsulin6.210.46.0 (42.1)75.5no family members tested
F113P210121717nononeinsulinN/AN/A6.3 (45.4)12.6multiple generations affected
F113P211434522.2nononediet6.99.26.3 (45.4)N/Amultiple generations affected
F116P21471919.8noheadache, elevated RROAD—metformin5.8146.8 (50.8)75.5cousin positive, parents not tested
F116P21591521.1nononediet5.86.46.5 (47.5)75.5cousin positive, parents not tested
F122P222142025noN/Adiet6.5N/A6.2 (44.3)75.5siblings positive, parents not tested
F122P223142424nononediet6.3N/AN/AN/Asiblings positive, parents not tested
F126P227143622.5noPCOSOAD—metformin5.9>115.8 (39.9)75.5no family members tested
F131P232192819.4nononenone8.4N/A6.8 (50.8)75.5no family members tested
F133P236131419nononediet6.49.46.4 (46.4)75.5multiple generations affected
F133P237111819nononeinsulinN/AN/A6.4 (46.4)8.2multiple generations affected
F133P240314221nononeOAD7.810.006.4 (46.4)58multiple generations affected
F133P241576338yesIHDOAD8.710N/AN/Amultiple generations affected
F145P25761215.2nononeinsulinN/AN/A7.1 (54.1)12.6multiple generations affected
F145P2583738N/AN/AN/AN/A7.37.85.8 (39.9)N/Amultiple generations affected
F145P259no diabetes2016N/AN/AnoneN/A7.05.9N/AN/Amultiple generations affected
F145P26045N/AN/AnonenoneN/A9.76.8 (50.8)N/Amultiple generations affected
F145P261394024.3noN/AN/A7.25.96.3 (45.4)N/Amultiple generations affected
F150P266355921.6nononeOAD—metformin10.1N/A7.4 (57.4)15.1parents not tested
F153P27191623.6nononediet6.912.06.2 (44.3)75.5no family members tested
F162P28091232.4yesacanthosis nigricansOAD—metforminN/AN/A6.5 (47.5)75.5multiple generations affected
F162P2813414.1noN/Adiet4.75.76.4 (46.4)75.5multiple generations affected
F162P282N/A2N/AN/AN/AN/AN/AN/AN/AN/Amultiple generations affected
F162P283no diabetes21N/AN/AN/Anone5.46.2N/AN/Amultiple generations affected
F163P28471129.0yesnonenone10.06.36.2 (44.3)75.5multiple generations affected
F163P28591323.5nononenone6.610.95.9 (41.0)75.5multiple generations affected
F163P286N/A43N/AN/AN/AN/AN/AN/AN/AN/Amultiple generations affected
F165P288101118.0noN/Adiet710.85.9 (41.0)75.5no family members tested
F167P290131319.2nononediet5.210.75.7 (38.8)75.5multiple generations affected
F167P292no diabetes48N/AN/AN/AN/AN/AN/AN/AN/Amultiple generations affected
F173P2981215noN/Adiet5.69.96.4 (46.4)75.5multiple generations affected
F173P2991633N/AN/AN/AinsulinN/AN/AN/AN/Amultiple generations affected
F187P3191416.5nononenone6.3—75.8—76.5 (47.5)75.5no family members tested
F191P32311216.8nononediet6.67.36.6 (48.6)75.5no family members tested
F197P335132721.9nononediet6.98.56.5 (47.5)75.5no family members tested
F200P33851817.7nononediet6.178.36.8 (50.8)75.5multiple generations affected
F200P339475123.9nononeOAD—metformin + sulphonylureaN/AN/AN/AN/Amultiple generations affected
F201P340233119.7nononeOAD—
sulphonylurea
6.611.26.1 (43.2)75.5multiple generations affected
F201P341576030.8yesN/Adiet6.914.56.3 (45.4)N/Amultiple generations affected
F201P342223523.1nononediet7.39.85.8 (39.9)75.5multiple generations affected
F202P3435617.0nononenone6.28.26.4 (46.4)75.5siblings positive, parents not tested
F202P34491015.4nononenone6.56.96.9 (51.9)75.5siblings positive, parents not tested
F205P34941016.5nononediet5.88.55.7 (38.8)75.5no family members tested
F209P35394329nononeOAD—metformin7.29.57.0 (53.0)75.5no family members tested
F213P357N/A1217.8nononediet7.18.66.2 (44.3)N/Amultiple generations affected
F213P358N/A34N/AN/AN/AdietN/AN/AN/AN/Amultiple generations affected
F216P361N/A1416.2nononediet5.65.96.3 (45.4)N/Ano family members tested
F219P364323925.2nononediet6.98.75.5 (36.6)62.4parents not tested
F227P37372125.7nononeinsulin7.014.76.1 (43.2)75.5multiple generations affected
F227P374N/A1515.5noN/AN/A6.8N/AN/AN/Amultiple generations affected
F227P377455133yesnoneOAD—metformin7.88.9N/AN/Amultiple generations affected
F244P394151617.6nononediet6.58.86.2 (44.3)75.5no family members tested
F246P3966719.9yesnonenone6.79.46.3 (45.4)75.5multiple generations affected
F246P398no diabetes43N/AN/AN/AN/A7.5N/A7.0 (53.0)N/Amultiple generations affected
F250P403N/A35N/AN/AcardiacN/AN/AN/AN/AN/Ano family members tested
F263P426183121.5noN/AOAD—metformin6.98.56.4 (46.4)75.5no family members tested
F272P435202217.4nononenone6.722.96.0 (42.1)75.5no family members tested
F273P436N/A1819.5noN/AN/A5.8N/AN/AN/Ano family members tested
F274P43751632.7yeshypertension, obesityOAD—metformin6.59.46.5 (47.5)75.5siblings positive, parents not tested
F274P4382716.7nononediet6.7N/A6.4 (46.4)75.5siblings positive, parents not tested
F275P43981016.3nononediet6.18.36.1 (43.2)75.5no family members tested
F280P444N/A10N/AN/AN/AN/AN/AN/AN/AN/Ano family members tested
F291P455101619.2nononeinsulin6.511.76.8 (50.8)4no family members tested
F296P4601318N/AN/AnoneinsulinN/AN/AN/AN/Ano family members tested
F306P4707814.6norepeated acute laryngitisnone6.10N/A6.0 (42.0)75.5no family members tested
F310P477141522.2noN/AN/AN/AN/A6.4 (46.4)75.5mother no carrier, father not tested
F314P4824614.9nononedietN/AN/A6.0 (42.1)75.5no family members tested
F316P488303720.6nononeOAD—metformin6.36.96.3 (45.4)35.8no family members tested
F349P532173920.6nononeOAD—metformin5.7N/A6.4 (46.4)75.5no family members tested
F353P536142326.7nononediet6.99.66.5 (47.5)75.5no family members tested
F373P55781819.2noN/Adiet5.795.6 (37.7)75.5no family members tested
F374P55821920noN/Adiet6.09.46.7 (49.7)75.5no family members tested
F375P559810normalnononediet7.99.56.7 (49.7)N/Ade novo
F381P570121221.2nononediet5.38.86.8 (50.8)75.5multiple generations affected
F381P57224124noN/AdietN/AN/AN/AN/Amultiple generations affected
F382P574131322nononediet7.79.86.3 (45.4)75.5multiple generations affected
F382P575N/A41N/AN/AN/AN/AN/AN/AN/AN/Amultiple generations affected
F382P577N/A61N/AN/AN/AN/AN/AN/AN/AN/Amultiple generations affected
F382P578N/A29N/AN/AN/AN/AN/AN/AN/AN/Amultiple generations affected
F389P586283120nononediet7.29.56.3 (45.4)62.4no family members tested
F400P598141821nononenone6.78.95.7 (38.8)75.5no family members tested
F403P601101115.1nononeinsulin6.011.06.3 (45.4)12.6mother no carrier, father not tested
F403P604no diabetes7N/AN/AN/AN/AN/AN/AN/AN/Amother no carrier, father not tested
F408P61051818.7nononeinsulin7.3N/A6.4 (46.4)1.9siblings positive, parents not tested
F408P611141417.9nononediet7.28.87.1 (54.1)75.5siblings positive, parents not tested
F411P614121214.7nononediet5.99.37.0 (53.0)75.5multiple generations affected
F411P616no diabetes11N/AN/AN/AN/AN/AN/AN/AN/Amultiple generations affected
F411P617no diabetes4226nononediet7.19.16.2 (44.3)N/Amultiple generations affected
F433P639N/A13N/AN/AN/AN/AN/AN/AN/AN/Ano family members tested
F434P640N/A10N/AN/AN/AN/AN/AN/AN/AN/Ano family members tested
F435P64171318nononeinsulinN/AN/A7.1 (54.1)8.2multiple generations affected
F435P642243724nononenoneN/AN/A7.2 (55.2)62.4multiple generations affected
F454P665101117.4nopossible coeliac diseasenone6.25.9N/AN/Ano family members tested
F455P66634N/AN/AN/Adiet4.912.76.1 (43.2)N/Amultiple generations affected
F455P667N/AN/AN/AN/AN/AN/AN/AN/AN/AN/Amultiple generations affected
F463P675202718.9nononeOAD—metformin + sulphonylurea7.2N/A6.6 (48.6)75.5no family members tested
F472P68412N/AN/AN/AN/A6.48.66.9 (51.9)N/Amultiple generations affected
F472P733N/A50N/AN/AN/AN/AN/AN/AN/AN/Amultiple generations affected
F482P6966628yesN/Adiet6.411.06.2 (44.3)75.5no family members tested
F499P713N/A21N/AN/AN/AN/AN/AN/AN/AN/Ano family members tested
Index patients are shown in bold. Age at diabetes: N/A—the patient has diabetes, but no information was received regarding the age of diagnosis; no diabetes—no information was given in the application form that the patient shows any signs of diabetes. dg—diagnosis; OAD—oral antidiabetic drug; IHD—Ischemic Heart Disease; PAD—Peripheral Arterial Disease; TIA—transient ischemic attack; PCOS—Polycystic Ovary Syndrome; RR—respiratory rate. * BMI data refers to the time of referral for genetic testing.
Table 5. The distribution of the types of therapy received before proper genetic diagnosis.
Table 5. The distribution of the types of therapy received before proper genetic diagnosis.
TherapyNumber of Patients
insulin19 (11.7%)
OAD—sulphonylurea2 (1.2%)
OAD—metformin19 (11.7%)
OAD—metformin and sulphonylurea2 (1.2%)
OAD—acarbose1 (0.6%)
other OAD2 (1.2%)
diet56 (34.4%)
no treatment24 (14.7%)
N/A38 (23.3%)
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Gaál, Z.; Szűcs, Z.; Kántor, I.; Luczay, A.; Tóth-Heyn, P.; Benn, O.; Felszeghy, E.; Karádi, Z.; Madar, L.; Balogh, I. A Comprehensive Analysis of Hungarian MODY Patients—Part II: Glucokinase MODY Is the Most Prevalent Subtype Responsible for about 70% of Confirmed Cases. Life 2021, 11, 771. https://0-doi-org.brum.beds.ac.uk/10.3390/life11080771

AMA Style

Gaál Z, Szűcs Z, Kántor I, Luczay A, Tóth-Heyn P, Benn O, Felszeghy E, Karádi Z, Madar L, Balogh I. A Comprehensive Analysis of Hungarian MODY Patients—Part II: Glucokinase MODY Is the Most Prevalent Subtype Responsible for about 70% of Confirmed Cases. Life. 2021; 11(8):771. https://0-doi-org.brum.beds.ac.uk/10.3390/life11080771

Chicago/Turabian Style

Gaál, Zsolt, Zsuzsanna Szűcs, Irén Kántor, Andrea Luczay, Péter Tóth-Heyn, Orsolya Benn, Enikő Felszeghy, Zsuzsanna Karádi, László Madar, and István Balogh. 2021. "A Comprehensive Analysis of Hungarian MODY Patients—Part II: Glucokinase MODY Is the Most Prevalent Subtype Responsible for about 70% of Confirmed Cases" Life 11, no. 8: 771. https://0-doi-org.brum.beds.ac.uk/10.3390/life11080771

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