Diagnosis of MODY in the Offspring of Parents with Insulin-dependent and Non-insulin-dependent Diabetes Mellitus

Guazzarotti, Laura; Fumelli, P.; Testa, I.; Pecora, Ricardo Augusto; Panicari, F; Bellanné‐Chantelot, Christine; Bartolotta, E

doi:10.1515/jpem.2001.14.s1.611

Cited by 8 publications

(5 citation statements)

References 19 publications

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“…We also found one novel synonymous exonic variant (p.A173A) with no predicted impact on protein function or mRNA splicing, which was therefore classified as a likely benign variant of no clinical significance. Seven of the variants have been reported previously in the literature (c.46‐2A>G, c.1254‐1G>C, p.K169R, p.R191Q, p.V367M, p.R275C and p.M393T) . The remaining five (p.F123S, p.L58P, p.G246A, p.F419C and p.S151C) are not listed in any publications collated by the online Human Gene Mutation Database and were therefore classified as novel (Table ).…”

Section: Resultsmentioning

confidence: 99%

“…Seven of the variants have been reported previously in the literature (c.46-2A>G, c.1254-1G>C, p.K169R, p.R191Q, p.V367M, p.R275C and p.M393T). 3,[11][12][13][14] The remaining five (p.F123S, p.L58P, p.G246A, p.F419C and p.S151C) are not listed in any publications collated by the online Human Gene Mutation Database and were therefore classified as novel ( Table 2). In addition, we identified a novel intronic variant, c.208 + 3A>T, of uncertain significance.…”

Section: Molecular Genetic Test Resultsmentioning

confidence: 99%

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GCK gene mutations are a common cause of childhood‐onset MODY (maturity‐onset diabetes of the young) in Turkey

Haliloğlu

Hysenaj

Atay

et al. 2016

Clinical Endocrinology

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SummaryObjectiveInactivating heterozygous mutations in the GCK gene are a common cause of MODY and result in mild fasting hyperglycaemia, which does not require treatment. We aimed to identify the frequency, clinical and molecular features of GCK mutations in a Turkish paediatric cohort.Design and PatientsFifty‐four unrelated probands were selected based on the following criteria: age of diagnosis ≤17 years, family history of diabetes in at least two generations, anti‐GAD/ICA negative, BMI<95.p and follow‐up with diet, oral antidiabetic drug or low‐dose insulin treatment (≤0·5U/kg/d). A MODY probability score (www.diabetesgenes.org) was calculated and 21 patients with a score ≥75%, HbA1c levels ≤7·5% (58·5 mmol/mol) and fasting blood glucose (FBG) levels 99–145 mg/dl (5·5–8·0 mmol/l) were selected for Sanger sequencing of the GCK gene. Targeted next‐generation sequencing for all known monogenic diabetes genes was undertaken for any patient without a GCK gene mutation.Results GCK gene mutations (pathogenic or likely pathogenic variants) and a novel intronic variant of uncertain significance (c.208 + 3A>T) were identified in 13/54 probands (24%). Twelve of these patients had a MODY probability score ≥75%. FBG level and 2‐h glucose level in OGTT were 123 ± 14 mg/dl (6·8 ± 0·7 mmol/l) (107–157 mg/dl) and 181 ± 30 mg/dl (10·1 ± 1·6 mmol/l) (136–247 mg/dl), respectively. Average of glucose increment in OGTT was 58 ± 27 mg/dl (3·2 ± 1·5 mmol/l) (19–120 mg/dl), and mean HbA1c level was 6·5 ± 0·5% (47·5 ± 5·5 mmol/mol) (5·9–7·6%). Five novel missense mutations were identified (p.F123S, p.L58P, p.G246A, p.F419C, and p.S151C). Two patients treated with low‐dose insulin before the molecular analysis were able to stop treatment.ConclusionsApproximately 1 in 4 MODY cases in this Turkish paediatric cohort have a GCK mutation. Selection of patients for GCK gene analysis using the MODY probability score was an effective way of identifying most (11/12) patients with a GCK mutation.

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Section: Resultsmentioning

confidence: 99%

Section: Molecular Genetic Test Resultsmentioning

confidence: 99%

GCK gene mutations are a common cause of childhood‐onset MODY (maturity‐onset diabetes of the young) in Turkey

Haliloğlu

Hysenaj

Atay

et al. 2016

Clinical Endocrinology

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“…P22 is compound heterozygous for two variants in GCK : p.Arg275Cys and Chr7:g.48309C > A/c.580‐3C > A. The p.Arg275Cys mutation has been previously described in heterozygosis in patients with the GCK‐MODY phenotype in Italian, Pakistani, Norwegian, and Turkish families 45–57 . This variant leads to increased enzyme degradation, increasing cellular apoptosis 52 .…”

Section: Discussionmentioning

confidence: 99%

“…The p.Arg275Cys mutation has been previously described in heterozygosis in patients with the GCK-MODY phenotype in Italian, Pakistani, Norwegian, and Turkish families. [45][46][47][48][49][50][51][52][53][54][55][56][57] This variant leads to increased enzyme degradation, increasing cellular apoptosis. 52 The g.48309C > A/c.…”

Section: Ptf1a (Nm_1781613)mentioning

confidence: 99%

Genetic and clinical features of neonatal and early onset diabetes mellitus in a tertiary center cohort in Brazil

et al. 2022

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Neonatal diabetes mellitus (NDM) is defined as the occurrence of severe hyperglycemia in infants under 6 months old and may be permanent (PNDM) or transient (TNDM).When diabetes is diagnosed at 6-12 months of age (early onset diabetes [EOD]), the etiology may be monogenic; however, most cases consist of type 1 diabetes mellitus (T1DM). Molecular diagnosis was determined in a cohort of 35 unrelated Brazilian patients with NDM or EOD based on targeted next-generation sequencing panel and/or chromosome 6q24 abnormalities. The impact of genetic testing on treatment and follow-up was evaluated. Overall, 24 patients had NDM: with 18 (75.0%) having PNDM, 5 TNDM (20.8%) and 1 case in which this information was unknown. Eleven patients had EOD. Genetic testing was positive in 20/24 patients with NDM (83.3%) and in 18.2% of cases of EOD. The commonest causes were ATP-sensitive potassium (KATP) channel genes, and GCK and IPEX mutations (37.1%, 11.4% and 5.7%, respectively). Patients with PNDM due to KCNJ11 and ABCC8 mutations transitioned successfully to sulfonylureas in almost 60% of cases, reinforcing the benefit of performing genetic testing in NDM as early as possible. This report refers to the largest series of cases of NDM (TNDM and PNDM) and EOD in Brazil in which patients were submitted to molecular investigation and in which the clinical impact of genetic diagnosis was also evaluated.

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“…The maturity onset diabetes of the young (MODY), is caused by mutations in the six known genes encoding the hepatocyte nuclear factor-4α (HNF-4α), glucokinase (GCK), hepatocyte nuclear factor-1α (HNF-1α), insulin promoter factor-1(IPF-1), hepatocyte nuclear factor-1β (HNF-1β) and NeuroD1 respectively [2]. The diagnosis of MODY is very important in children and adolescent diabetic patients [3,4]. Although the true relative prevalence of six distinct MODY subtypes is unknown and varies substantially in studies in various populations [5][6][7][8][9][10], mutations in the genes encoding HNF1α and GCK are the most prevalent.…”

Section: Introductionmentioning

confidence: 99%

Analysis of the glucokinase gene in Iranian families with maturity onset diabetes of the young

Javadi¹,

Rafatpanah²,

Taghavi³

et al. 2013

JDM

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Non insulin dependent diabetes mellitus (NIDDM)as a most common form of diabetes is a major public health problem; there is a subgroup of NIDDM patients who develop the disease at an early age and show a dominant mode of inheritance. This type is nominates Maturity onset diabetes of the young (MODY). The prevalence of MODY is difficult to access, and patients with MODY genes mutations are often identified during routine screening for other purposes. MODY2 was linked to glucokinase gene (GCK) mutations, and accounted for 8% to 56% of MODY, with the highest prevalence found in the southern Europe. The aim of this study was to examine the prevalence and nature of mutations in GCK gene in Iranian paients. We have screened GCK mutations by polymerase chain reaction (PCR); single stranded conformation polymorphism (SSCP) technique in 12 Iranian families with clinical diagnosis of MODY, included 30 patients (8 males and 22 females) and their 21 family members. PCR products with abnormal mobility in denaturing gradient gel electrophoresis (DGGE) were directly sequenced. We identified 6 novel mutations in GCK gene in Iranian families (corresponding to 36.6% prevalence). Our findings and the last study on MODY1 highlight that in addition to GCK, other MODY genes such as MODY3 and MODYX may play a significant role in diabetes characterized by monogenic autosomal dominant transmission. There is an important point that the genetic recognation can be used to pre-symptomatically identify family members at risk for developing MODY.

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Diagnosis of MODY in the Offspring of Parents with Insulin-dependent and Non-insulin-dependent Diabetes Mellitus

Cited by 8 publications

References 19 publications

GCK gene mutations are a common cause of childhood‐onset MODY (maturity‐onset diabetes of the young) in Turkey

GCK gene mutations are a common cause of childhood‐onset MODY (maturity‐onset diabetes of the young) in Turkey

Genetic and clinical features of neonatal and early onset diabetes mellitus in a tertiary center cohort in Brazil

Analysis of the glucokinase gene in Iranian families with maturity onset diabetes of the young

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