Next generation sequencing targeted gene panel in Greek MODY patients increases diagnostic accuracy

Tatsi, Elizabeth‐Barbara; Kanaka‐Gantenbein, Christina; Scorilas, Andreas; Chrousos, George P.; Sertedaki, Amalia

doi:10.1111/pedi.12931

Cited by 32 publications

(16 citation statements)

References 59 publications

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“…Currently it is suggested that genetic tests for MODY should be performed when paediatric diabetes is diagnosed, together with modest hyperglycaemia and absence of all four islet autoantibodies (antibodies against GAD, insulinoma antigen-2, zinc transporter 8 and insulin), but there is no standardised diagnostic algorithm [ 12 , 132 , 133 ]. At present, genetic tests for MODY are conducted with NGS methodology due to lower costs and increased diagnostic accuracy [ 134 ].…”

Section: Diagnosis and Current Treatment Optionsmentioning

confidence: 99%

Maturity Onset Diabetes of the Young—New Approaches for Disease Modelling

Skoczek

Dulak

Kachamakova‐Trojanowska

2021

IJMS

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Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous group of monogenic endocrine disorders that is characterised by autosomal dominant inheritance and pancreatic β-cell dysfunction. These patients are commonly misdiagnosed with type 1 or type 2 diabetes, as the clinical symptoms largely overlap. Even though several biomarkers have been tested none of which could be used as single clinical discriminator. The correct diagnosis for individuals with MODY is of utmost importance, as the applied treatment depends on the gene mutation or is subtype-specific. Moreover, in patients with HNF1A-MODY, additional clinical monitoring can be included due to the high incidence of vascular complications observed in these patients. Finally, stratification of MODY patients will enable better and newer treatment options for MODY patients, once the disease pathology for each patient group is better understood. In the current review the clinical characteristics and the known disease-related abnormalities of the most common MODY subtypes are discussed, together with the up-to-date applied diagnostic criteria and treatment options. Additionally, the usage of pluripotent stem cells together with CRISPR/Cas9 gene editing for disease modelling with the possibility to reveal new pathophysiological mechanisms in MODY is discussed.

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Section: Diagnosis and Current Treatment Optionsmentioning

confidence: 99%

Maturity Onset Diabetes of the Young—New Approaches for Disease Modelling

Skoczek

Dulak

Kachamakova‐Trojanowska

2021

IJMS

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“…In Greece, the GCK-MODY ratio is reported to be somewhat lower with only 54% and HNF1A -MODY with 12% [ 49 ]. A very recent Greek study puts the diagnostic rate at 20% [ 50 ]. These data show that the inclusion criteria for testing, the methodology used (i.e., number of analysed genes if gene panel testing is applied and whether copy number variation analysis is performed or not) might significantly affect the pickup rate.…”

Section: Discussionmentioning

confidence: 99%

A Comprehensive Analysis of Hungarian MODY Patients—Part I: Gene Panel Sequencing Reveals Pathogenic Mutations in HNF1A, HNF1B, HNF4A, ABCC8 and INS Genes

Gaál

Szücs

Kántor

et al. 2021

Life

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Maturity-onset diabetes of the young (MODY) has about a dozen known causal genes to date, the most common ones being HNF1A, HNF4A, HNF1B and GCK. The phenotype of this clinically and genetically heterogeneous form of diabetes depends on the gene in which the patient has the mutation. We have tested 450 Hungarian index patients with suspected MODY diagnosis with Sanger sequencing and next-generation sequencing and found a roughly 30% positivity rate. More than 70% of disease-causing mutations were found in the GCK gene, about 20% in the HNF1A gene and less than 10% in other MODY-causing genes. We found 8 pathogenic and 9 likely pathogenic mutations in the HNF1A gene in a total of 48 patients and family members. In the case of HNF1A-MODY, the recommended first-line treatment is low dose sulfonylurea but according to our data, the majority of our patients had been on unnecessary insulin therapy at the time of requesting their genetic testing. Our data highlights the importance of genetic testing in the diagnosis of MODY and the establishment of the MODY subtype in order to choose the most appropriate treatment.

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“…Although MODY accounts for 1-5% of all diabetic cases, molecular genetic diagnosis of MODY is necessary for optimal long-term treatment, prognosis, and especially genetic counseling. Studies have shown that pathogenic variants are mostly detected in the MODY-related genes GCK, HNF1A and HNF4A and that such variants in GCK and HNF1A are responsible for approximately 70% of all MODY cases [15]. It is believed that many genes associated with MODY have not been identi ed yet [16].…”

Section: Discussionmentioning

confidence: 99%

Study of Thirteen Causal Genes in Turkish Patients with Clinically Suspected Maturity-Onset Diabetes of the Young (MODY) using a Targeted Next-Generation Sequencing Panel

Doğan¹,

Eröz

Bolu

et al. 2021

Preprint

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Background: Maturity-onset diabetes of the young (MODY), which is the most common cause of monogenic diabetes, has an autosomal dominant pattern of inheritance and exhibits marked clinical and genetic heterogeneity. The aim of the current study was to investigate molecular defects in patients with clinically suspected MODY using a next-generation sequencing (NGS)-based targeted gene panel. Candidate patients with clinical suspicion of MODY and their parents were included in the study. Molecular genetic analyses were performed on genomic DNA by using NGS. A panel of thirteen MODY-related genes involving ABCC8, BLK, CEL, GCK, HNF1A, HNF1B, HNF4A, INS, KCNJ11, KLF11, NEUROD1, PAX4, PDX1 was designed and subsequently implemented to screen 44 patients for genetic variants. Ten different pathogenic or likely pathogenic variants were identified in MODY-suspected patients, with a diagnostic rate of 22.7%. Eight variants of uncertain significance were also detected. Four novel pathogenic or likely pathogenic variants were detected in the genes GCK (c.1301G>T [p.Cys434Phe]), HNF1A (c.505_506delAA [p.Lys169AlafsTer18]), ABCC8 (c.3584C>T [p.Thr1195Ile]), and CEL (c.679-1G>A). Intriguingly, we were able to detect variants associated with rare forms of MODY in our study population. Our results suggest that in heterogenous diseases such as MODY, NGS analysis enables accurate identification of underlying molecular defects in a timely and cost-effective manner. Although MODY accounts for 1–2% of all diabetic cases, molecular genetic diagnosis of MODY is necessary for optimal long-term treatment and prognosis as well as for effective genetic counseling.

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Next generation sequencing targeted gene panel in Greek MODY patients increases diagnostic accuracy

Cited by 32 publications

References 59 publications

Maturity Onset Diabetes of the Young—New Approaches for Disease Modelling

Maturity Onset Diabetes of the Young—New Approaches for Disease Modelling

A Comprehensive Analysis of Hungarian MODY Patients—Part I: Gene Panel Sequencing Reveals Pathogenic Mutations in HNF1A, HNF1B, HNF4A, ABCC8 and INS Genes

Study of Thirteen Causal Genes in Turkish Patients with Clinically Suspected Maturity-Onset Diabetes of the Young (MODY) using a Targeted Next-Generation Sequencing Panel

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