The Genetic Spectrum of Maturity-Onset Diabetes of the Young (MODY) in Qatar, a Population-Based Study

Elashi, Asma A.; Toor, Salman M; Diboun, Ilhame; Al-Sarraj, Yasser; Taheri, Shahrad; Suhre, Karsten; Abou‐Samra, Abdul Badi

doi:10.3390/ijms24010130

Cited by 10 publications

(7 citation statements)

References 52 publications

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“…Heterozygous RFX6 pathogenic variants have been linked to MODY with reduced penetrance in humans (15)(16)(17)(18)(19)(20)(21). Moreover, genome-wide association studies (GWAS) have associated variants of RFX6 with T2D (22,23).…”

Section: Introductionmentioning

confidence: 99%

RFX6haploinsufficiency predisposes to diabetes through impaired beta cell functionality

Ibrahim,

Balboa,

Saarimäki-Vire

et al. 2023

Preprint

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Regulatory factor X 6 (RFX6) is indispensable for pancreatic endocrine development and differentiation. The RFX6 protein-truncating variant p.His293LeufsTer7 is significantly enriched in the Finnish population with almost 1:250 individuals as a carrier. Importantly, the FinnGen study indicates a high predisposition for heterozygous carriers to develop type 2 diabetes (T2D) and gestational diabetes. To understand the role of this variant in β-cell development and function, we generated allelic series of isogenic pluripotent stem cell models and directed them into pancreatic islet lineages (SC-islets). Expectedly,in-vitromodels of the homozygousRFX6−/−variant failed to generate pancreatic endocrine cells, recapitulating the phenotype in Mitchell-Riley syndrome. Notably, heterozygousRFX6+/−derived SC-islets showed reduced β-cell maturation markers and calcium oscillations, resulting in defective insulin secretion, without affecting β-cell number or insulin content. The reduced insulin secretion is sustained duringin-vivoimplantation studies, consistent with the susceptibility of the carriers to develop diabetes.TeaserModelingRFX6-assocciated neonatal and type-2 diabetes using allelic series stem cell-derived isletsin-vitroandin-vivo.

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Section: Introductionmentioning

confidence: 99%

RFX6haploinsufficiency predisposes to diabetes through impaired beta cell functionality

Ibrahim,

Balboa,

Saarimäki-Vire

et al. 2023

Preprint

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“…Moreover, the signi cant load of genetic homozygosity due to the high rate of consanguineous marriages in the MENA region makes a remarkable distinctive genetic spectrum in this area [5,16]. Due to the unknown etiology and underreporting of MODY in the MENA region, lucrative academic and clinical research on MODY has been pursued in the Middle East [35,37].…”

Section: Discussionmentioning

confidence: 99%

“…Overall, discrepancies in reported variants among our MODY cases compared to those from Qatar could be attributed to variations in the study design. Despite the population-based design of both studies, as MODY typically shows an AD inheritance, a family-based design is necessary to better peruse familial transmission of the disease in family members [37].…”

Section: Discussionmentioning

confidence: 99%

From Genes to Diagnosis: Examining the Clinical and Genetic Spectrum of Maturity-Onset Diabetes of the Young (MODY) in TCGS

Asgarian,

Lanjanian,

Anaraki

et al. 2024

Preprint

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Maturity-onset diabetes of the young (MODY) is an uncommon monogenic type of diabetes mellitus. Detecting genetic biomarkers for MODY is a necessity for precise diagnosis and treatment. The majority of MODY genetic predisposition has been documented in European populations and a lack of information is present in Iranians which leads to misdiagnosis as a consequence of defects in unknown variants. In this study, using genetic variant information of 20,002 participants from the family-based TCGS (Tehran cardiometabolic genetic study) cohort, we evaluated the genetic spectrum of MODY in Iran. We concentrated on 14 previously discovered and two novel MODY-causing genes (RFX6 and NKX6-1) that were thought to be responsible for MODY. To find disease-causing mutations, genetic variants were evaluated for their pathogenicity. We discovered 6 mutations that were previously reported in the ClinVar as pathogenic/likely pathogenic (P/LP) for MODY in 45 participants from 24 families. Three potentially novel MODY-causing mutations were also identified, which showed complete disease penetrance (100%) in 10 subjects from 5 families. This is the first family-based study to define the genetic spectrum and estimate the prevalence of MODY in the Iran. The newly discovered mutations need to be investigated by additional studies.

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“…Variants of the BLK gene (rs766934515) were identified in five patients, and mutations of the GCK gene were present in four of the patients. Other rare mutations were located in the HNF4A , GCK , KLF11 , and ABCC8 genes [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

The Importance of Molecular Genetic Testing for Precision Diagnostics, Management, and Genetic Counseling in MODY Patients

Butnariu,

Bizim,

Oltean

et al. 2024

IJMS

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Maturity-onset diabetes of the young (MODY) is part of the heterogeneous group of monogenic diabetes (MD) characterized by the non-immune dysfunction of pancreatic β-cells. The diagnosis of MODY still remains a challenge for clinicians, with many cases being misdiagnosed as type 1 or type 2 diabetes mellitus (T1DM/T2DM), and over 80% of cases remaining undiagnosed. With the introduction of modern technologies, important progress has been made in deciphering the molecular mechanisms and heterogeneous etiology of MD, including MODY. The aim of our study was to identify genetic variants associated with MODY in a group of patients with early-onset diabetes/prediabetes in whom a form of MD was clinically suspected. Genetic testing, based on next-generation sequencing (NGS) technology, was carried out either in a targeted manner, using gene panels for monogenic diabetes, or by analyzing the entire exome (whole-exome sequencing). GKC-MODY 2 was the most frequently detected variant, but rare forms of KCNJ11-MODY 13, specifically, HNF4A-MODY 1, were also identified. We have emphasized the importance of genetic testing for early diagnosis, MODY subtype differentiation, and genetic counseling. We presented the genotype–phenotype correlations, especially related to the clinical evolution and personalized therapy, also emphasizing the particularities of each patient in the family context.

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The Genetic Spectrum of Maturity-Onset Diabetes of the Young (MODY) in Qatar, a Population-Based Study

Cited by 10 publications

References 52 publications

RFX6haploinsufficiency predisposes to diabetes through impaired beta cell functionality

RFX6haploinsufficiency predisposes to diabetes through impaired beta cell functionality

From Genes to Diagnosis: Examining the Clinical and Genetic Spectrum of Maturity-Onset Diabetes of the Young (MODY) in TCGS

The Importance of Molecular Genetic Testing for Precision Diagnostics, Management, and Genetic Counseling in MODY Patients

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