Neonatal outcome and diabetes course in children with GCK-MODY born from women with GCK-MODY.
Kopacz-Petranyuk Katarzyna,Brandt-Varma Agnieszka,Buraczewska Marta,Wołoszyn-Durkiewicz Anna,Peczyńska Jagoda,Preis Krzysztof,Jarosz-Chobot Przemysława,Szadkowska Agnieszka,Młynarski Wojciech,Myśliwiec Małgorzata
Pediatric endocrinology, diabetes, and metabolism
INTRODUCTION:Gestational diabetes is one of the most common medical disorders and may cause numerous of maternal and foetal complications, such as: preterm births, congenital defects, hypertrophic cardiomyopathy, metabolic changes, and macrosomia in neonates. One of the types of diabetes that may clinically manifest in pregnancy is GCK-MODY, caused by mutations in the glucokinase (GCK) gene. AIM OF THE STUDY:The aim of the study was to assess the impact of diabetes during pregnancy in women with GCK-MODY on their children's health outcome and to determine the clinical and biochemical characteristics of children delivered by patients with GCK-MODY. MATERIAL AND METHODS:Study was multicentre, involving 50 children from paediatric diabetology departments in Gdansk, Katowice, Bialystok, and Lodz. The risk of GCK-MODY was evaluated on the basis of the medical history of the patient, the clinical course of the disease, and laboratory tests performed during diagnostic procedures. Data concerning family history, mothers' health status, course of pregnancy, and perinatal period was collected. RESULTS:The study showed that among children with glucokinase mutation, born by mothers affected with GCK-MODY, 62% received 10 points in Apgar score in the first minute of life, whereas 92% (n = 46) obtained 10 points in Apgar score in the fifth minute of life. The average age of diagnosis of GCK-MODY in children was 8.25 ±4.76 years, and the average HbA1c during diagnosis was 6.43 ±0.71%. Statis-tically significant difference between the absence of macrosomia (birth weight > 91st percentile) in children with GCK-MODY diabetes in comparison to the general paediatric population (p = 0.0229) was observed. CONCLUSION:According to the presented study, possible consequences of GCK-MODY during pregnancy on foetal development are generally less severe and may differ from those characteristic for other types of diabetes. Children born by mothers with diabetes should be followed up regarding glucose disorders. Further investigation of particular phenotypes of GCK-MODY, depending on the type of inherited mu-tation in mothers and their children, is required.
[MODY2: Clinical and molecular genetic characteristics of 13 cases of the disease. The first description of MODY in Russia].
Dedov I I,Zubkova N A,Arbatskaya N Y,Akopova A G,Tyul'pakov A N
Maturity-onset diabetes of the young (MODY) is a clinically heterogenic group of diseases, with an autosomal dominant mode of inheritance and gene mutations resulting in dysfunction of pancreatic β cells. The type of diabetes and further treatment policy can be reliably determined on the basis of the data of a molecular genetic study that confirms gene mutations. Today there are known mutations of 8 genes, of which glucokinase (GCK) gene mutation that leads to the development of MODY2 and occurs most frequently. The spread of this mutation among DM patients in our country has not been studied. The diagnosis of MODY2 was established in 13 members of 5 families with the clinical picture typical of this type. The molecular genetic study revealed 4 new and 1 earlier described mutations. The findings extend ideas on the molecular bases of MODY, which creates conditions for improving the diagnosis of this disease, genetic counseling and the development of pathogenetically founded approaches to treatment.
Long-term follow-up and mutation analysis of 27 chinese cases of congenital hyperinsulinism.
Su Chang,Gong Chunxiu,Sanger Paul,Li Wenjing,Wu Di,Gu Yi,Cao Bingyan
Hormone research in paediatrics
OBJECTIVES:Long-term clinical follow-up and mutation analysis were performed in 27 Chinese congenital hyperinsulinism patients. METHOD:27 hypoglycemia patients were diagnosed with CHI within 2 years of age. The long-term clinical outcome was analyzed and mutation analysis of 5 hyperinsulinism candidate genes was performed. RESULTS:The median onset age of hypoglycemia in the patients was 60 days; 11 patients showed hypoglycemic symptoms in the neonatal stage, and hypoglycemia in most of the patients was first expressed as a seizure. Blood was collected during the hypoglycemic episode and insulin levels were significantly elevated. ABCC8, KCNJ11, GCK, HNF4a and GLUD1 genes were screened for mutation analysis. 14 mutations in ABCC8 or KCNJ11 genes in 12 cases were identified (44%). 57% (8/14) of the mutations have not been reported before. 83% (10/12) of the patients have a monoallelic mutation. 58% of these 12 patients were predicted to be focal. 73% of the patients without KATP channel mutations were sensitive to diazoxide. 26 patients were followed over a period of 1-13 years. 50% of all 27 patients showed brain impairment. CONCLUSIONS:Chinese CHI patients are similar to other ethnic groups in terms of prevalence of KATP-HI, onset age, severity of hypoglycemia and treatment. Mutations in ABCC8 and KCNJ11 are common causes of CHI in Chinese patients. Mutation analysis showed more novel and monoallele mutations in KATP genes.
Genetic testing of GCK-MODY identifies a novel pathogenic variant in a Chinese boy with early onset hyperglycemia.
Poon Kok-Siong,Tan Karen Mei-Ling,Koay Evelyn Siew-Chuan,Sng Andrew
Human genome variation
Glucokinase-maturity-onset diabetes of the young (GCK-MODY or MODY 2), caused by a heterozygous inactivating variant in the ( gene, is a common form of MODY. Here, we present a case of GCK-MODY in a young Chinese boy, his sister and his father with a novel pathogenic variant in exon 8 of the gene, NM_000162.5:c.1015del, p.(Glu339Argfs*14), which is predicted to cause a significant change in protein structure and function.
Genetic and bioinformatics analysis of four novel GCK missense variants detected in Caucasian families with GCK-MODY phenotype.
Costantini S,Malerba G,Contreas G,Corradi M,Marin Vargas S P,Giorgetti A,Maffeis C
Heterozygous loss-of-function mutations in the glucokinase (GCK) gene cause maturity-onset diabetes of the young (MODY) subtype GCK (GCK-MODY/MODY2). GCK sequencing revealed 16 distinct mutations (13 missense, 1 nonsense, 1 splice site, and 1 frameshift-deletion) co-segregating with hyperglycaemia in 23 GCK-MODY families. Four missense substitutions (c.718A>G/p.Asn240Asp, c.757G>T/p.Val253Phe, c.872A>C/p.Lys291Thr, and c.1151C>T/p.Ala384Val) were novel and a founder effect for the nonsense mutation (c.76C>T/p.Gln26*) was supposed. We tested whether an accurate bioinformatics approach could strengthen family-genetic evidence for missense variant pathogenicity in routine diagnostics, where wet-lab functional assays are generally unviable. In silico analyses of the novel missense variants, including orthologous sequence conservation, amino acid substitution (AAS)-pathogenicity predictors, structural modeling and splicing predictors, suggested that the AASs and/or the underlying nucleotide changes are likely to be pathogenic. This study shows how a careful bioinformatics analysis could provide effective suggestions to help molecular-genetic diagnosis in absence of wet-lab validations.
[A novel mutation W257R in gene discovered from a Chinese patient with maturity onset diabetes of the young].
Hong Pingping,Guo Bingjie,Lin Li,Lin Xihua,Zhou Jiaqiang
Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences
Maturity onset diabetes of the young (MODY) is a monogenic autosomal dominant inherited disease. Its clinical manifestations are asymptomatic with slightly elevated fasting blood glucose and few complications. This paper reports a novel mutation W257R in glucokinase () gene from a Chinese patient with MODY. Heterozygous mutation c.769T>C (p.W257R) in exon 7 of gene (Chr744187343) was found in the proband, her father and brother. This W257R mutation was first reported in Chinese population.
Genetic counseling in monogenic diabetes GCK MODY.
Skała-Zamorowska Eliza,Deja Grażyna,Borowiec Maciej,Fendler Wojciech,Małachowska Beata,Kamińska Halla,Młynarski Wojciech,Jarosz-Chobot Przemysława
Pediatric endocrinology, diabetes, and metabolism
INTRODUCTION:Genetic testing in families with monogenic GCK MODY has predictive, diagnostic, and preventive utility. Predictive tests relate to people who have no features of the disorder themselves at the time of testing. Diagnostic tests relate to family members who have been previously diagnosed with diabetes mellitus or glucose metabolism disturbances. The preventive value of genetic testing for families is to raise awareness of the circumstances leading to glucose metabolism disorders. AIM:The detection of mutation carriers among family members of patients with GCK MODY and the determination of the clinical significance of the genetic test result. METHODS:The study group included 27 families of adolescent patients with GCK MODY (39 (75%) of parents and 19 (73.08%) of siblings) monitored in the Department of Pediatrics, Endocrinology and Diabetes and in the Diabetes Clinic of John Paul II Upper Silesian Child Health Centre in Katowice in the years 2007-2012. Subjects underwent a blood sample drawing for genetic and biochemical testing. RESULTS:Through the genetic diagnostics we diagnosed GCK MODY in 14 (63.64%) mothers, 6 (35.29%) fathers and in 7 (36,84%) siblings. Genetic testing has contributed to the detection of 7 (26.92%) asymptomatic carriers of GCK gene mutation among parents and 3 (15,79%) asymptomatic carriers among siblings declaring no carbohydrate metabolism disturbances (before genetic testing there were no indications suggesting carbohydrate metabolism disturbances; OGTT were performed after positive genetic testing). CONCLUSIONS:Each case of mutation detection, which is the cause of monogenic diabetes in a patient, justifies the genetic testing in other members of his/her family. Awareness of the genetic status may allow sick family member to confirm the diagnosis, while asymptomatic mutation carriers could benefit from an early clinical observation. Consequently, in each case it gives an opportunity to take diagnostic and therapeutic measures in accordance with the current state of knowledge.
Copy Number Variation in GCK in Patients With Maturity-Onset Diabetes of the Young.
Berberich Amanda J,Huot Céline,Cao Henian,McIntyre Adam D,Robinson John F,Wang Jian,Hegele Robert A
The Journal of clinical endocrinology and metabolism
PURPOSE:Next generation sequencing (NGS) methods to diagnose maturity-onset diabetes of the young (MODY), a monogenic autosomal dominant cause of diabetes, do not typically detect large-scale copy number variations (CNVs). New techniques may allow assessment for CNVs using output data from targeted NGS, without requiring additional sequencing. Using this technique, two kindreds of patients presenting with features of MODY were found to bear the same heterozygous large-scale deletion in GCK. METHODS:Patients suspected of having MODY but with negative targeted NGS pathogenic variant calling were reanalyzed using the CNV caller tool (VarSeq v1.4.3). Two patients were identified as having a possible heterozygous whole exon deletion affecting exon 1 of GCK. For confirmation and determination of the exact breakpoints, whole exome sequencing followed by Sanger sequencing were used. Familial samples from both affected and nonaffected first-degree relatives were then analyzed for each proband. RESULTS:A heterozygous whole-exon deletion spanning 4763 bp affecting the entire exon 1 of GCK was detected in two apparently unrelated patients with clinical features of MODY. This deletion showed segregation concordance across generations in affected and nonaffected family members. CONCLUSIONS:Our findings confirm the utility of applying the CNV caller tool to screen for CNVs in GCK from NGS data. In so doing, we identified a deletion of exon 1 of GCK as likely causal for MODY. Our data indicate that incorporating CNV analysis routinely when assessing for MODY via targeted NGS may increase diagnostic yield and reduce false negative genetic testing rates.
GCK-MODY in the US National Monogenic Diabetes Registry: frequently misdiagnosed and unnecessarily treated.
Carmody David,Naylor Rochelle N,Bell Charles D,Berry Shivani,Montgomery Jazzmyne T,Tadie Elizabeth C,Hwang Jessica L,Greeley Siri Atma W,Philipson Louis H
AIMS:GCK-MODY leads to mildly elevated blood glucose typically not requiring therapy. It has been described in all ethnicities, but mainly in Caucasian Europeans. Here we describe our US cohort of GCK-MODY. METHODS:We examined the rates of detection of heterozygous mutations in the GCK gene in individuals referred to the US Monogenic Diabetes Registry with a phenotype consistent with GCK-MODY. We also assessed referral patterns, treatment and demography, including ethnicity, of the cohort. RESULTS:Deleterious heterozygous GCK mutations were found in 54.7 % of Registry probands selected for GCK sequencing for this study. Forty-nine percent were previously unnecessarily treated with glucose-lowering agents, causing hypoglycemia and other adverse effects in some of the subjects. The proportion of probands found to have a GCK mutation through research-based testing was similar across each ethnic group. However, together African-American, Latino and Asian subjects represented only 20.5 % of screened probands and 17.2 % of those with GCK-MODY, despite higher overall diabetes prevalence in these groups. CONCLUSIONS:Our data show that a high detection rate of GCK-MODY is possible based on clinical phenotype and that prior to genetic diagnosis, a large percentage are inappropriately treated with glucose-lowering therapies. We also find low minority representation in our Registry, which may be due to disparities in diagnostic diabetes genetic testing and is an area needing further investigation.
Clinical application of ACMG-AMP guidelines in HNF1A and GCK variants in a cohort of MODY families.
Santana L S,Caetano L A,Costa-Riquetto A D,Quedas E P S,Nery M,Collett-Solberg P,Boguszewski M C S,Vendramini M F,Crisostomo L G,Floh F O,Zarabia Z I,Kohara S K,Guastapaglia L,Passone C G B,Sewaybricker L E,Jorge A A L,Teles M G
Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. GCK -MODY and HNF1A -MODY are the prevalent subtypes. Currently, there is growing concern regarding the correct interpretation of molecular genetic findings. The American College of Medical Genetics and Genomics (ACMG) updated guidelines to interpret and classify molecular variants. This study aimed to determine the prevalence of MODY ( GCK / HNF1A ) in a large cohort of Brazilian families, to report variants related to phenotype, and to classify them according to ACMG guidelines. One hundred and nine probands were investigated, 45% with clinical suspicion of GCK -MODY and 55% with suspicion of HNF1A -MODY. Twenty-five different variants were identified in GCK gene (30 probands-61% of positivity), and 7 variants in HNF1A (10 probands-17% of positivity). Fourteen of them were novel (12- GCK /2- HNF1A ). ACMG guidelines were able to classify a large portion of variants as pathogenic (36%- GCK /86%- HNF1A ) and likely pathogenic (44%- GCK /14%- HNF1A ), with 16% (5/32) as uncertain significance. This allows us to determine the pathogenicity classification more efficiently, and also reinforces the suspected associations with the phenotype among novel variants.
Incidence of and MODY Variants in a South African Population.
Matsha Tandi E,Raghubeer Shanel,Tshivhase Abegail M,Davids Saarah F G,Hon Gloudina M,Bjørkhaug Lise,Erasmus Rajiv T
The application of clinical genetics
Background and Aim:Maturity-onset diabetes of the young (MODY) is the result of single gene variants. To date, fourteen different MODY subtypes have been described. Variants in genes coding for glucokinase (, MODY2) and hepatic nuclear factor 1 alpha (, MODY3) are most frequently encountered. MODY patients are often misdiagnosed with type 1 or type 2 diabetes, resulting in incorrect treatment protocols. At the time of reporting, no data are available on MODY prevalence in populations from Africa. Our study aimed to investigate and report on the incidence of MODY-related variants, specifically variants, in a population from the Western Cape. Methods:Study participants were recruited (1643 in total, 407 males, 1236 females) and underwent anthropometric tests. Thereafter, blood was collected, and real-time PCR was used to screen for specific variants in and genes. Results:Ninety-seven individuals (5.9%) were identified with a specific gene polymorphism (rs1169288) and twelve (0.9%) with a polymorphism (rs4607517). Conclusion:In total, 6.6% of the study population expressed MODY variants. To our knowledge, we are the first to report on MODY incidence in Africa. This research provides the basis for MODY incidence studies in South Africa, as well as data on non-Caucasian populations.
Management and pregnancy outcomes of women with GCK-MODY enrolled in the US Monogenic Diabetes Registry.
Dickens Laura T,Letourneau Lisa R,Sanyoura May,Greeley Siri Atma W,Philipson Louis H,Naylor Rochelle N
AIMS:GCK-MODY is characterized by mild hyperglycemia. Treatment is not required outside of pregnancy. During pregnancy, insulin treatment is recommended if second trimester fetal ultrasound monitoring shows macrosomia, suggesting the fetus has not inherited the GCK gene. There are limited data about GCK-MODY management in pregnancy. The aim of this study was to examine clinical management and pregnancy outcomes amongst women with a known diagnosis of GCK-MODY. METHODS:In this observational, cross-sectional study, a survey was distributed via Redcap to women ≥ 18 years enrolled in the University of Chicago Monogenic Diabetes Registry (n = 94). All or part of the survey was completed by 54 women (128 pregnancies). RESULTS:There were 78 term births (61%), 15 pre-term births (12%), and 24 miscarriages (19%). Of the 39 pregnancies where insulin was given, 22 (56%) had occasional or frequent hypoglycemia including 9 with severe hypoglycemia. Average birth weight for full-term GCK-affected infants was significantly less in cases of maternal insulin treatment versus no treatment (2967 and 3725 g, p = 0.005). For GCK-unaffected infants, conclusions are limited by small sample size but large for gestational age (LGA) was common with maternal insulin treatment (56%) and no treatment (33%), p = 0.590. CONCLUSIONS:The observed miscarriage rate was comparable to the background US population rate (15-20%). Patients treated with insulin experienced a 23% incidence of severe hypoglycemia and lower birth weights were observed in the insulin-treated, GCK-affected neonates. These data support published guidelines of no treatment if the fetus is suspected to have inherited GCK-MODY and highlight the importance of additional studies to determine optimal pregnancy management for GCK-MODY, particularly among unaffected fetuses.
Identification and functional analysis of GCK gene mutations in 12 Chinese families with hyperglycemia.
Wang Zhixin,Diao Chengming,Liu Yijing,Li Mingmin,Zheng Jia,Zhang Qian,Yu Miao,Zhang Huabing,Ping Fan,Li Ming,Xiao Xinhua
Journal of diabetes investigation
AIMS/INTRODUCTION:To investigate the clinical and genetic characteristics of Chinese patients with a phenotype consistent with maturity-onset diabetes of the young type 2 and explore the pathogenic mechanism of their hyperglycemia. MATERIALS AND METHODS:We studied 12 probands and their extended families referred to our center for screening mutations in the glucokinase gene (GCK). Clinical data were collected and genetic analysis was carried out. The recombinant wild-type and mutant glucokinase were generated in Escherichia coli. The kinetic parameters and thermal stability of the enzymes were determined in vitro. RESULTS:In the 12 families, 11 GCK mutations (R43C, T168A, K169N, R191W, Y215X, E221K, M235T, R250H, W257X, G261R and A379E) and one variant of uncertain significance (R275H) were identified. R191W was detected in two unrelated families. Of the 11 GCK mutations, three mutations (c.507G>C, K169N; c.645C>A, Y215X; c.771G>A, W257X; NM_000162.3, NP_000153.1) are novel. Basic kinetics analysis explained the pathogenicity of the five mutants (R43C, K169N, R191W, E221K and A379E), which showed reduced enzyme activity with relative activity indexes between ~0.001 and 0.5 compared with the wild-type (1.0). In addition, the thermal stabilities of these five mutants were also decreased to varying degrees. However, for R250H and R275H, there was no significant difference in the enzyme activity and thermal stability between the mutants and the wild type. CONCLUSIONS:We have identified 11 GCK mutations and one variant of uncertain significance in 12 Chinese families with hyperglycemia. For five GCK mutations (R43C, K169N, R191W, E221K and A379E), the changes in enzyme kinetics and thermostability might be the pathogenic mechanisms by which mutations cause hyperglycemia.
MODY2 in Asia: analysis of GCK mutations and clinical characteristics.
Zhou Yuan,Wang ShengNan,Wu Jing,Dong JianJun,Liao Lin
Aims:Heterozygous inactivating mutations in the GCK gene cause the familial, mild fasting hyperglycaemia named MODY2. Many patients with MODY2 in Asia have delayed timely treatment because they did not receive the correct diagnosis. This study aims to analyze the clinical characteristics and GCK mutations in Asian MODY2. Methods:We have collected 110 Asian patients with MODY2 from the PubMed, Embase, Medline, Web of Science, CNKI, and Wanfang with the following search terms: 'maturity-onset diabetes of the young' OR 'MODY' OR 'maturity-onset diabetes of the young type 2' OR 'MODY2' OR 'GCK-DM' OR 'GCK-MODY'. Both mutations of GCK and clinical characteristics of MODY2 were analyzed. Results:There were 96 different mutations that occurred in coding regions and non-coding regions. Exon 5 and 7 were the most common location in coding regions and missense was the primary mutation type. The proportion of probands younger than 25 was 81.8%, and 81.4% of the probands had family history of hyperglycaemia. Ninety percent and 93% of Asian MODY2 probands exhibited mild elevation in FPG (5.4-8.3 mmol/L) and HbA1c (5.6-7.6%), respectively. Conclusions:In most Asian patients, MODY2 occurred due to GCK mutation in coding regions, and exon 5 and 7 were the most common locations. FPG, HbA1c, and familial diabetes were important reference indicators for diagnosing MODY2. Altogether, the study indicates that for the young onset of diabetes with mild elevated blood glucose and HbA1c and family history of hyperglycaemia, molecular genetic testing is suggested in order to differentiate MODY2 from other types of diabetes earlier.
NGS Analysis Revealed Digenic Heterozygous and Variants in a Child with Mild Hyperglycemia: A Case Report.
Iafusco Fernanda,Maione Giovanna,Mazzaccara Cristina,Di Candia Francesca,Mozzillo Enza,Franzese Adriana,Tinto Nadia
Diagnostics (Basel, Switzerland)
Monogenic diabetes (MD) represents a heterogeneous group of disorders whose most frequent form is maturity-onset diabetes of the young (MODY). MD is predominantly caused by a mutation in a single gene. We report a case of a female patient with suspected MD and a positive family history for diabetes and obesity. In this patient, two gene variants have been identified by next-generation sequencing (NGS): one in the Glucokinase ( gene reported in the Human Gene Mutation Database (HGMD) and in the literature associated with GCK/MODY, and the other in the hepatocyte nuclear factor 1A () gene not previously described. The variant was also identified in the hyperglycemic father, whereas the variant was present in the mother. This new case of digenic variants identified in a hyperglycemic subject, evidences the importance of NGS analysis in patients with suspected MD. In fact, this methodology will allow us to both increase the number of diagnoses and to identify mutations in more than one gene, with a better understanding of the genetic cause, and the clinical course, of the disease.
Clinical implications of the glucokinase impaired function - GCK MODY today.
Hulín J,Škopková M,Valkovičová T,Mikulajová S,Rosoľanková M,Papcun P,Gašperíková D,Staník J
Heterozygous inactivating mutations of the glucokinase (GCK) gene are causing GCK-MODY, one of the most common forms of the Maturity Onset Diabetes of the Young (MODY). GCK-MODY is characterized by fasting hyperglycemia without apparent worsening with aging and low risk for chronic vascular complications. Despite the mild clinical course, GCK-MODY could be misdiagnosed as type 1 or type 2 diabetes. In the diagnostic process, the clinical suspicion is often based on the clinical diagnostic criteria for GCK-MODY and should be confirmed by DNA analysis. However, there are several issues in the clinical and also in genetic part that could complicate the diagnostic process. Most of the people with GCK-MODY do not require any pharmacotherapy. The exception are pregnant women with a fetus which did not inherit GCK mutation from the mother. Such a child has accelerated growth, and has increased risk for diabetic foetopathy. In this situation the mother should be treated with substitutional doses of insulin. Therefore, distinguishing GCK-MODY from gestational diabetes in pregnancy is very important. For this purpose, special clinical diagnostic criteria for clinical identification of GCK-MODY in pregnancy are used. This review updates information on GCK-MODY and discusses several currently not solved problems in the clinical diagnostic process, genetics, and treatment of this type of monogenic diabetes.
Genetic and clinical characteristics of Chinese children with Glucokinase-maturity-onset diabetes of the young (GCK-MODY).
Li Xiuzhen,Ting Tzer Hwu,Sheng Huiying,Liang Cui Li,Shao Yongxian,Jiang Minyan,Xu Aijing,Lin Yunting,Liu Li
BACKGROUND:There is scarcity of information on the clinical features and genetics of glucokinase-maturity-onset diabetes of the young (GCK-MODY) in China. The aim of the study was to investigate the clinical and molecular characteristics of Chinese children with GCK-MODY. METHODS:Eleven children with asymptomatic hyperglycemia and clinically suspected GCK-MODY were identified from the database of children with diabetes in the biggest children's hospital in South China. Clinical data were obtained from medical records. Blood was collected from the patients and their parents for glucokinase (GCK) gene analysis. Parents without diabetes were tested for fasting glucose and HbA1c. Clinical information and blood for GCK gene analysis were obtained from grandparents with diabetes. GCK gene mutational analysis was performed by polymerase chain reaction and direct sequencing. Patients without a GCK gene mutation were screened by targeted next-generation sequencing (NGS) technology for other MODY genes. RESULTS:Nine children tested positive for GCK gene mutations while two were negative. The nine GCK-MODY patients were from unrelated families, aged 1 month to 9 years and 1 month at first detection of hyperglycaemia. Fasting glucose was elevated (6.1-8.5 mmol/L), HbA1c 5.2-6.7% (33.3-49.7 mmol/mol), both remained stable on follow-up over 9 months to 5 years. Five detected mutations had been previously reported: p.Val182Met, c.679 + 1G > A, p.Gly295Ser, p.Arg191Gln and p.Met41Thr. Four mutations were novel: c.483 + 2 T > A, p.Ser151del, p.Met57GlyfsX29 and p.Val374_Ala377del. No mutations were identified in the other two patients, who were also tested by NGS. CONCLUSIONS:GCK gene mutations are detected in Chinese children and their family members with typical clinical features of GCK-MODY. Four novel mutations are detected.
[Hyperglycemia caused by mutation of GCK gene in 10 patients analysis of clinical and mutation characteristics].
Zhang J,Yuan K,Ding S X,Kong Y M,Zhu J F,Fang Y L,Liang L,Fu J F,Wang C L
Zhonghua er ke za zhi = Chinese journal of pediatrics
To explore the gene mutation characteristics and detailed clinical presentations of hyperglycemia caused by GCK mutations in 10 patients. The clinical and follow-up data of 10 patients with hyperglycemia caused by mutation of GCK gene were reviewed. The patients were ascertained between January 1, 2014 and August 31, 2018 at the Department of Pediatrics, the First Affiliated Hospital of Zhejiang University and Ningbo Women & Children's Hospital. Clinical data were collected, including age, gender, main complaint, family history, fasting blood glucose, fasting blood insulin, 2-hour blood glucose, 2-hour blood insulin after oral glucose tolerance test, glycosylated hemoglobin, anti-glutamic acid decarboxylase antibody and body mass index. Mutations of GCK gene were detected by Sanger sequencing or high-throughput sequencing of diabetes-related genes in the patients and their family members. There were ten patients, 8 of them were male, 2 were female.The ages at diagnosis varied between 4.7 to 12.3 years. The patients usually did not have obvious clinical symptoms of diabetes mellitus. Most of them were unexpectedly found to have hyperglycemia and with impaired glucose metabolism in three consecutive generations. The fasting blood glucose of patients was 6.8-7.7 mmol/L, 2-hour postprandial blood glucose was 7.8-11.6 mmol/L. Fasting blood insulin was 0.5-8.5 mU/L, glucose tolerance test results showed that 2 h postprondial blood insulin was 1.3-55.4 mU/L. The level of glycosylated hemoglobin was 6.1%-6.8%. Anti-glutamic acid decarboxylase antibody was negative in all patients. The GCK mutations identified in patients and one of their parents were located at exon5 (4 cases), exon9 (2 cases), exon2 (1 case), exon4 (1 case), exon6 (1 case) and exon7 (1 case). Most of the hyperglycemia patients caused by GCK mutations did not have typical clinical symptoms of diabetes. The fasting blood glucose was slightly elevated. Abnormal glucose tolerance test results were found in all 10 patients. Three consecutive generations of family had impaired glucose metabolism. GCK mutations located at exon 5 were common in 10 cases. There was no correlation between type of mutations and plasma glucose levels in domestic and international researches. When fasting glucose was found abnormal in clinic, a complete family history should be taken and the GCK gene should be sequenced to confirm the diagnosis in time.
Monogenic diabetes caused by GCK gene mutation is misdiagnosed as gestational diabetes - A multicenter study in Portugal.
Lima Ferreira Joana,Voss Gina,Sá Couto Adelina,Príncipe Rosa Maria
Diabetes & metabolic syndrome
AIMS:Monogenic diabetes is an underdiagnosed type of diabetes mellitus, which can be harmful in pregnancy. We aim to estimate the prevalence of diabetes caused by the mutation of the glucokinase gene (GCK-MODY) in pregnant women diagnosed with gestational diabetes mellitus (GDM) and to characterize pregnant women with this suspicion. METHODS:A multicenter observational study with data prospectively collected from pregnancies with GDM was conducted. Two groups of pregnant women were considered: those with GCK-MODY criteria and those without those criteria. RESULTS:Of 18421 women with GDM, 3.6% (n = 730) had the GCK-MODY clinical criteria. A prevalence of 1.5% of GCK-MODY is estimated in women with GDM in Portugal, which is higher than in Northern European countries. Suspected GCK-MODY women had statistically higher odds of having neonates below the 25th percentile (OR = 1.23, 95%CI = 1.04-1.46, p = 0.016) and having prediabetes and diabetes in postpartum reclassification (OR = 2.11, 95%CI = 1.55-2.82, p < 0.001 and OR = 5.96, 95%CI = 3.38-10.06, p < 0.001, respectively). CONCLUSIONS:Higher odds of neonates below the 25th percentile was probably due to excessive insulin treatment in cases where both the mother and the fetus have the mutation. It is essential to consider the diagnosis of GCK-MODY in all women with GDM criteria for better management of diabetes in pregnancy.
Molecular changes in the Glucokinase gene (GCK) associated with the diagnosis of Maturity Onset Diabetes of the Young (MODY) in pregnant women and newborns.
Lepore Carolina,Damaso Enio,Suazo Veridiana,Queiroz Rosane,Junior Raphael Liberatore,Moisés Elaine
Current diabetes reviews
BACKGROUND:Diabetes Mellitus is the most common metabolic alteration in gestation. Monogenic diabetes or Maturity-Onset Diabetes of the Young (MODY) consists in a subtype caused by primary defect in insulin secretion determined by dominant autosomal inheritance. OBJECTIVES:To analyze molecular changes of the Glucokinase gene (GCK) in pregnant women with hyperglycemia during gestation and in their neonates. Case study and Methods: We collected 201 blood samples, 128 from pregnant patients diagnosed with hyperglycemia and 73 from umbilical cord blood from neonates of the respective patients. We performed DNA extraction and polymerase chain reaction (PCR) to identify molecular changes in the GCK gene. RESULTS:In a total of 201 samples (128 from mothers and 73 from neonates), we found changes in 21 (10.6%), 12 maternal samples (6.0%) and 9 neonatal samples (4.5%). DNA sequencing identified two polymorphisms and one deleterious MODY GCK-diagnostic mutation. CONCLUSIONS:The prevalence of molecular changes of the Glucokinase gene (GCK) and the deleterious MODY GCK-diagnostic mutation were, respectively, 9.3% and 0.7% in women with hyperglycemia during gestation and 12.5% and 1.3% in their neonates. The deleterious MODY GCK mutation identified is associated reduction in GCK activity and hyperglycemia. In the others molecular changes identified despite not having clinical significance, it was not possible to exclude phenotypic change. Therefore, these changes may interfere with the management and clinical outcome of the patients.
Analysis of the GCK gene in 79 MODY type 2 patients: A multicenter Turkish study, mutation profile and description of twenty novel mutations.
Aykut Ayça,Karaca Emin,Onay Hüseyin,Gökşen Damla,Çetinkalp Şevki,Eren Erdal,Ersoy Betül,Çakır Esra Papatya,Büyükinan Muammer,Kara Cengiz,Anık Ahmet,Kırel Birgül,Özen Samim,Atik Tahir,Darcan Şükran,Özkınay Ferda
Maturity onset diabetes is a genetic form of diabetes mellitus characterized by an early age at onset and several etiologic genes for this form of diabetes have been identified in many patients. Maturity onset diabetes type 2 [MODY2 (#125851)] caused by mutations in the glucokinase gene (GCK). Although its prevalence is not clear, it is estimated that 1%-2% of patients with diabetes have the monogenic form. The aim of this study was to evaluate the molecular spectrum of GCK gene mutations in 177 Turkish MODY type 2 patients. Mutations in the GCK gene were identified in 79 out of 177. All mutant alleles were identified, including 45 different GCK mutations, 20 of which were novel.