scholarly journals Tunisian Maturity-Onset Diabetes of the Young: A Short Review and a New Molecular and Clinical Investigation

2021 ◽  
Vol 12 ◽  
Author(s):  
Mariam Moalla ◽  
Wajdi Safi ◽  
Maab Babiker Mansour ◽  
Mohamed Hadj Kacem ◽  
Mona Mahfood ◽  
...  
Keyword(s):  
Autoimmune Diabetes ◽  
Clinical Investigation ◽  
Direct Sequencing ◽  
Short Review ◽  
Tunisian Population ◽  
Maturity Onset Diabetes ◽  
Clinical Criteria ◽  
Pathogenic Variants ◽  
Onset Diabetes ◽  
And Function

Introduction/AimsMaturity-Onset Diabetes of the Young (MODY) is a monogenic non-autoimmune diabetes with 14 different genetic forms. MODY-related mutations are rarely found in the Tunisian population. Here, we explored MODY related genes sequences among seventeen unrelated Tunisian probands qualifying the MODY clinical criteria.Materials and MethodsThe GCK and HNF1A genes were systematically analyzed by direct sequencing in all probands. Then, clinical exome sequencing of 4,813 genes was performed on three unrelated patients. Among them, 130 genes have been reported to be involved in the regulation of glucose metabolism, β-cell development, differentiation and function. All identified variants were analyzed according to their frequencies in the GnomAD database and validated by direct sequencing.ResultsWe identified the previously reported GCK mutation (rs1085307455) in one patient. The clinical features of the MODY2 proband were similar to previous reports. In this study, we revealed rare and novel alterations in GCK (rs780806456) and ABCC8 (rs201499958) genes with uncertain significance. We also found two likely benign alterations in HNF1A (rs1800574) and KLF11 (rs35927125) genes with minor allele frequencies similar to those depicted in public databases. No pathogenic variants have been identified through clinical exome analysis.ConclusionsThe most appropriate patients were selected, following a strict clinical screening approach, for genetic testing. However, the known MODY1-13 genes could not explain most of the Tunisian MODY cases, suggesting the involvement of unidentified genes in the majority of Tunisian affected families.

scholarly journals Comprehensive genomic analysis identifies pathogenic variants in maturity-onset diabetes of the young (MODY) patients in South India

2018 ◽  
Vol 19 (1) ◽  
Author(s):  
Viswanathan Mohan ◽  
Venkatesan Radha ◽  
Thong T. Nguyen ◽  
Eric W. Stawiski ◽  
Kanika Bajaj Pahuja ◽  
...  
Keyword(s):  
South India ◽  
Genomic Analysis ◽  
Maturity Onset Diabetes ◽  
Pathogenic Variants ◽  
Onset Diabetes

Targeted next generation sequencing in patients with maturity-onset diabetes of the young (MODY)

2018 ◽  
Vol 31 (12) ◽  
pp. 1295-1304 ◽  
Author(s):  
Taha R. Özdemir ◽  
Özgür Kırbıyık ◽  
Bumin N. Dündar ◽  
Ayhan Abacı ◽  
Özge Ö. Kaya ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Maturity Onset Diabetes ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
Onset Diabetes ◽  
Frequent Mutations ◽  
Standards And Guidelines ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Abstract Background Maturity-onset diabetes of the young (MODY) is a common form of monogenic diabetes. Fourteen genes have been identified, each leading to cause a different type of MODY. The aims of this study were to reveal both known and novel variants in MODY genes in patients with MODY using targeted next generation sequencing (NGS) and to present the genotype-phenotype correlations. Methods Mutation analysis of MODY genes (GCK, HNF1A, HNF4A, HNF1B, ABCC8, INS and KCNJ11) was performed using targeted NGS in 106 patients with a clinical diagnosis of MODY. The variants were evaluated according to American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines recommendations. Results A total of 18 (17%) variants were revealed among all patients. Seven variants in GCK, six in HNF4A, four in HNF1A and one in ABCC8 genes were found. Eight of them were previously published and 10 of them were assessed as novel pathogenic or likely pathogenic variants. Conclusions While the most frequent mutations are found in the HNF1A gene in the literature, most of the variants were found in the GCK gene in our patient group using the NGS method, which allows simultaneous analysis of multiple genes in a single panel.

scholarly journals Chondromalacia patellae: current options and emerging cell therapies

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Weitao Zheng ◽  
Hanluo Li ◽  
Kanghong Hu ◽  
Liming Li ◽  
Mingjian Bei
Keyword(s):  
Clinical Investigation ◽  
Symptomatic Relief ◽  
Young Patients ◽  
Patellofemoral Instability ◽  
Cartilage Regeneration ◽  
Short Review ◽  
Cell Therapies ◽  
Chondromalacia Patellae ◽  
Cartilage Lesions ◽  
And Function

AbstractChondromalacia patellae (CMP), also known as runner’s knee, typically occurs in young patients, which is characterized by anterior knee pain (AKP) that is associated with visible changes in patellar cartilage. The initial pathological changes include cartilage softening, swelling, and edema. CMP is caused by several factors, including trauma, increased cartilage vulnerability, patellofemoral instability, bony anatomic variations, abnormal patellar kinematics, and occupation hazards. CMP may be reversible or may progress to develop patellofemoral osteoarthritis. Quadriceps wasting, patellofemoral crepitus, and effusion are obvious clinical indications. Additionally, radiological examinations are also necessary for diagnosis. Magnetic resonance imaging (MRI) is a non-invasive diagnostic method, which holds a promise in having the unique ability to potentially identify cartilage lesions. Modalities are conventionally proposed to treat cartilage lesions in the PF joint, but none have emerged as a gold standard, neither to alleviated symptoms and function nor to prevent OA degeneration. Recently, researchers have been focused on cartilage-targeted therapy. Various efforts including cell therapy and tissue emerge for cartilage regeneration exhibit as the promising regime, especially in the application of mesenchymal stem cells (MSCs). Intra-articular injections of variously sourced MSC are found safe and beneficial for treating CMP with improved clinical parameters, less invasiveness, symptomatic relief, and reduced inflammation. The mechanism of MSC injection remains further clinical investigation and is tremendously promising for CMP treatment. In this short review, etiology, MRI diagnosis, and treatment in CMP, especially the treatment of the cell-based therapies, are reviewed.

scholarly journals 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

2021 ◽  
Author(s):  
Mustafa Dogan ◽  
Recep Eroz ◽  
Semih Bolu ◽  
Hüseyin Yüce ◽  
Alper Gezdirici ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Molecular Genetic ◽  
Maturity Onset Diabetes ◽  
Next Generation ◽  
Molecular Defects ◽  
Pathogenic Variants ◽  
Onset Diabetes ◽  
Effective Manner ◽  
Long Term Treatment ◽  
Generation Sequencing

Abstract 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.

scholarly journals Heterozygous RFX6 protein truncating variants are associated with Maturity-Onset Diabetes of the Young (MODY) with reduced penetrance

2017 ◽  
Author(s):  
Kashyap A Patel ◽  
Jarno Kettunen ◽  
Markku Laakso ◽  
Alena Stančáková ◽  
Thomas W Laver ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Gastric Inhibitory Polypeptide ◽  
Monogenic Diabetes ◽  
Human Pancreas ◽  
Maturity Onset Diabetes ◽  
Discovery Cohort ◽  
Cell Dysfunction ◽  
Onset Diabetes ◽  
Reduced Penetrance ◽  
And Function

AbstractFinding new genetic causes of monogenic diabetes can help to understand development and function of the human pancreas. We aimed to find novel protein–truncating variants causing Maturity–Onset Diabetes of the Young (MODY), a subtype of monogenic diabetes. We used a combination of next–generation sequencing of MODY cases with unknown aetiology along with comparisons to the ExAC database to identify new MODY genes. In the discovery cohort of 36 European patients, we identified two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants were enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio, OR=131, P=l×l0‐4). We found similar results in non–Finnish European (n=348, OR=43, P=5×l0‐5) and Finnish (n=80, OR=22, P=1×l0‐6) replication cohorts. The overall meta–analysis OR was 34 (P=l×l0‐16). RFX6 heterozygotes had reduced penetrance of diabetes compared to common HNF1A and HNF4A–MODY mutations (27%, 70% and 55% at 25 years of age, respectively). The hyperglycaemia resulted from beta–cell dysfunction and was associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.

scholarly journals Maturity-onset diabetes of the young type 5 a MULTISYSTEMIC disease: a CASE report of a novel mutation in the HNF1B gene and literature review

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Juan Camilo Mateus ◽  
Carolina Rivera ◽  
Miguel O’Meara ◽  
Alex Valenzuela ◽  
Fernando Lizcano
Keyword(s):  
Diabetes Mellitus ◽  
Novel Mutation ◽  
Maturity Onset Diabetes ◽  
Family History Of Diabetes ◽  
Multiple Organs ◽  
Onset Diabetes ◽  
Multisystem Involvement ◽  
Multisystemic Disease ◽  
History Of ◽  
And Function

Abstract Background Diabetes mellitus with autosomal dominant inheritance, such as maturity-onset diabetes of the young (MODY), is a genetic form of diabetes mellitus. MODY is a type of monogenic diabetes mellitus in which multiple genetic variants may cause an alteration to the functioning of beta cells. The three most known forms of MODY are caused by modifications to the hnf4a, gck, and hnf1a genes. However, other MODY variants can cause multiple alterations in the embryonic development of the endoderm. This is the case in patients presenting with MODY5, who have a mutation of the hepatic nuclear factor 1B (hnf1b) gene. Case presentation We present the clinical case of a 15 year-old patient with a family history of diabetes mellitus and a classical MODY type 5 (MODY5) phenotype involving the pancreas and kidney, with a novel, unreported mutation in the hnf1b gene. Conclusions MODY5 is characterised by a mutation in the hnf1b gene, which plays an important role in the development and function of multiple organs. It should be suspected in patients with unusual diabetes and multisystem involvement unrelated to diabetes. Graphical abstract

scholarly journals Maturity-Onset Diabetes of the Young (MODY) in Portugal: Novel GCK, HNFA1 and HNFA4 Mutations

2020 ◽  
Vol 9 (1) ◽  
pp. 288
Author(s):  
Maria I. Alvelos ◽  
Catarina I. Gonçalves ◽  
Eduarda Coutinho ◽  
Joana T. Almeida ◽  
Margarida Bastos ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Bioinformatics Analysis ◽  
Clinical Presentation ◽  
Maturity Onset Diabetes ◽  
Portuguese Population ◽  
Clinical Criteria ◽  
Onset Diabetes ◽  
Insulin Dependence ◽  
Functional Consequences ◽  
Hnf1a Gene

Maturity-onset diabetes of the young (MODY) is a frequently misdiagnosed type of diabetes, which is characterized by early onset, autosomal dominant inheritance, and absence of insulin dependence. The most frequent subtypes are due to mutations of the GCK (MODY 2), HNF1A (MODY 3), and HNF4A (MODY 1) genes. We undertook the first multicenter genetic study of MODY in the Portuguese population. The GCK, HNF1A, and HNF4A genes were sequenced in 46 unrelated patients that had at least two of the three classical clinical criteria for MODY (age at diagnosis, family history, and clinical presentation). The functional consequences of the mutations were predicted by bioinformatics analysis. Mutations were identified in 23 (50%) families. Twelve families had mutations in the GCK gene, eight in the HNF1A gene, and three in the HNF4A gene. These included seven novel mutations (GCK c.494T>C, GCK c.563C>G, HNF1A c.1623G>A, HNF1A c.1729C>G, HNF4A c.68delG, HNF4A c.422G>C, HNF4A c.602A>C). Mutation-positive patients were younger at the time of diagnosis when compared to mutation-negative patients (14.3 vs. 23.0 years, p = 0.011). This study further expands the spectrum of known mutations associated with MODY, and may contribute to a better understanding of this type of diabetes and a more personalized clinical management of affected individuals.

scholarly journals Causal variants in Maturity Onset Diabetes of the Young (MODY) – A systematic review

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ibrar Rafique ◽  
Asif Mir ◽  
Muhammad Arif Nadeem Saqib ◽  
Muhammad Naeem ◽  
Luc Marchand ◽  
...  
Keyword(s):  
Middle Eastern ◽  
Maturity Onset Diabetes ◽  
Dominant Type ◽  
Pathogenic Variants ◽  
Search Terms ◽  
Onset Diabetes ◽  
Causal Variants ◽  
Autosomal Dominant Type

Abstract Background Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant type of diabetes. Pathogenic variants in fourteen genes are reported as causes of MODY. Its symptoms overlap with type 1 and type 2 diabetes. Reviews for clinical characteristics, diagnosis and treatments are available but a comprehensive list of genetic variants, is lacking. Therefore this study was designed to collect all the causal variants involved in MODY, reported to date. Methods We searched PubMed from its date of inception to December 2019. The search terms we used included disease names and name of all the known genes involved. The ClinVar database was also searched for causal variants in the known 14 MODY genes. Results The record revealed 1647 studies and among them, 326 studies were accessed for full-text. Finally, 239 studies were included, as per our inclusion criteria. A total of 1017 variants were identified through literature review and 74 unpublished variants from Clinvar database. The gene most commonly affected was GCK, followed by HNF1a. The traditional Sanger sequencing was used in 76 % of the cases and 65 % of the studies were conducted in last 10 years. Variants from countries like Jordan, Oman and Tunisia reported that the MODY types prevalent worldwide were not common in their countries. Conclusions We expect that this paper will help clinicians interpret MODY genetics results with greater confidence. Discrepancies in certain middle-eastern countries need to be investigated as other genes or factors, like consanguinity may be involved in developing diabetes.

scholarly journals Genetic testing of GCK-MODY identifies a novel pathogenic variant in a Chinese boy with early onset hyperglycemia

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Kok-Siong Poon ◽  
Karen Mei-Ling Tan ◽  
Evelyn Siew-Chuan Koay ◽  
Andrew Sng
Keyword(s):  
Genetic Testing ◽  
Protein Structure ◽  
Early Onset ◽  
Structure And Function ◽  
Pathogenic Variant ◽  
Maturity Onset Diabetes ◽  
Protein Structure And Function ◽  
Onset Diabetes ◽  
Significant Change ◽  
And Function

AbstractGlucokinase-maturity-onset diabetes of the young (GCK-MODY or MODY 2), caused by a heterozygous inactivating variant in the Glucokinase (GCK) 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 GCK gene, NM_000162.5:c.1015del, p.(Glu339Argfs*14), which is predicted to cause a significant change in protein structure and function.

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