The Mutation Spectrum of Rare Variants in the Gene of Adenosine Triphosphate (ATP)-Binding Cassette Subfamily C Member 8 in Patients with a MODY Phenotype in Western Siberia

Ivanoshchuk, D.; Shakhtshneider, E.; Михайлова, С. В.; Ovsyannikova, Alla; Rymar, O. D.; Валеев, Э. С.; Орлов, П. С.; Воевода, М. И.

doi:10.3390/jpm13020172

Cited by 2 publications

(1 citation statement)

References 49 publications

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“…Another case of compound heterozygosis was also described by Ivanoshchuk et al, who identified the co-inheritance of variant c.1562G>A (p.Arg521Gln) in the ABCC8 gene (ATPbinding cassette transporter subfamily C member 8) and of variant c.160C>T (p.Arg54*) in the HNF1A gene, respectively associated with MODY 12 and MODY 3, in a diabetic patient and his mother in Western Siberia. While c.160C>T in HFN1A is already defined as pathogenic, Arg521Gln in ABCC8, instead, is characterized by "conflicting interpretations of pathogenicity" or "uncertain significance" (44)…”

Section: Pcbd1 (Pterin-4 Alpha-carbinolamine Dehydratase 1)mentioning

confidence: 99%

Moody Only Monogenic? A Narrative Review of the Rare and Low-Penetrant Genetic Variants

Hasballa,

Maggi

2023

Preprint

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Introduction: Maturity-onset diabetes of the young (MODY) represents the most frequent form of monogenic diabetes mellitus (DM), currently classified in 14 distinct subtypes according to single gene mutations involved in the differentiation and function of pancreatic β-cells. Case report: The female patient at the age of 16 years old was diagnosed with non-autoimmune DM with glycated haemoglobin (HbA1c) value of 6.5%. After 6 years of dietary and lifestyle interventions due to the worsening of the glycometabolic profile, oral hypoglicemic therapy was initiated including at first only metformin, and subsequently also sulfonylureas and DPP-IV inhibitor. 11 years after diagnosis glargine insulin was started, associated 3 years later with Lispro insulin because of the worsening of the post-prandial glycaemia. According to the genetic testing a compound heterozygosis of two novel variants of uncertain/unknown clinical significance of BLK and RFX6 genes, respectively c.1013T>C (Ile338Thr) and c.1072G>A (Val358Ile), was identified. The RFX6 variant was also detected in the patient’s mother genome, while the BLK variant in her father’s. Discussion: Up to 11% of MODY has unknown etiology, suggesting that the genetic landscape is still to be explored. Recently, novel causal genes, involved in the differentiation and function of β-cells, have been identified such as RFX6, NKX2.2, NKX6.1, WFS1 and PCBD1. Genetic and clinical features of MODY variants remain highly heterogeneous, with no direct genotype-phenotype correlation especially in the low-penetrant subtypes. Thus, the aim of our paper is to present additionally to such rare case of a compound heterozygosity BLK/RFX6 underlying MODY, also a brief review of literature focused on the rare and reduced-penetrant variants, as well as on some controversies regarding this subtype of monogenic diabetes. Conclusions: Due to the limited data available, the assessment of MODY related-genes pathogenicity remains challenging especially in the setting of rare and low-penetrant subtypes. In consideration of the crucial importance of an accurate diagnosis, prognosis and management of MODY, more studies are warranted to further investigate its genetic landscape, the genotype-phenotype correlation, as well as the pathogenetic contribution of the non-genetic modifiers in this cohort of patients.

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Section: Pcbd1 (Pterin-4 Alpha-carbinolamine Dehydratase 1)mentioning

confidence: 99%

Moody Only Monogenic? A Narrative Review of the Rare and Low-Penetrant Genetic Variants

Hasballa,

Maggi

2023

Preprint

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Genetic and Clinical Characterization of Patients with HNF1B-Related MODY in Croatia

Baretić

Caban

Sertić

2023

JPM

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Background: Mutation of the gene encoding Hepatocyte Nuclear transcription Factor-1 Beta (HNF1B) causes a rare monogenetic subtype of Maturity-Onset Diabetes of the Young (MODY). HNF1B-related MODY results in the dysfunction of multiple organ systems. However, genetic analysis enables personalized medicine for patients and families. Aims: To understand the clinical characteristics and explore the gene mutations in Croatian patients. Methods: This was a retrospective observational study of individuals (and their relatives) who were, due to the clinical suspicion of MODY, referred to the Department of Laboratory Diagnostics at the University Hospital Centre Zagreb for genetic testing. Results: A total of 118 participants, 56% females, were screened. Seven patients (three females) from five families were identified to have HNF1B-related MODY. The median age at diagnosis was 31 (11–45) years, the median c-peptide was 0.8 (0.55–1.39) nmol/L, the median HbA1c was 9.1 (5.7–18.4)%, and the median BMI was 22.9 kg/m2 (17–24.6). Patients had a variety of clinical manifestations; kidney disease was not as frequent as liver lesions, neuropsychiatric symptoms, hyperlipidemia, hyperuricemia, and hypomagnesemia. We identified two new pathogenic mutations (c.1006C > G protein p.His336Asp on exon 4 and c.1373T > G p protein Val458Gly on exon 7). Conclusions: In a study involving Croatian patients, new genetic (two previously unknown mutations) and clinical (diverse range of clinical presentations) aspects of HNF1B-related MODY were found.

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The Mutation Spectrum of Rare Variants in the Gene of Adenosine Triphosphate (ATP)-Binding Cassette Subfamily C Member 8 in Patients with a MODY Phenotype in Western Siberia

Cited by 2 publications

References 49 publications

Moody Only Monogenic? A Narrative Review of the Rare and Low-Penetrant Genetic Variants

Moody Only Monogenic? A Narrative Review of the Rare and Low-Penetrant Genetic Variants

Genetic and Clinical Characterization of Patients with HNF1B-Related MODY in Croatia

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