Monogenic Childhood Diabetes: Dissecting Clinical Heterogeneity by Next-Generation Sequencing in Maturity-Onset Diabetes of the Young

Demirci, Deniz; Darendelıler, Feyza; Poyrazoğlu, Şükran; Al, Aslı Derya Kardelen; Gül, Nurdan; Tütüncü, Yıldız; Gulfidan, Gizem; Arğa, Kazım Yalçın; Cacina, Canan; Öztürk, Oğuz; Yilmaz-Aydogan, Hülya; Satman, İlhan

doi:10.1089/omi.2021.0081

Cited by 14 publications

(6 citation statements)

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“…It is notable that our findings using statistical method help underscore some of the prior evidence on the causality of MODY candidate genes and question others. Prior evidence has described variable levels of evidence for MODY susceptibility genes 14–16 HNF1A, HNF4A, GCK, HNF1B, ABCC8, KCNJ11 and INS have been thought to be the more common well‐established forms of MODY 16,17 . Of these well‐established genes, this study found convincing statistical evidence to support HNF1A, HNF4A, GCK, HNF1B and KCNJ11 .…”

Section: Discussionsupporting

confidence: 55%

“…It is notable that our findings using statistical method help underscore some of the prior evidence on the causality of MODY candidate genes and question others. Prior evidence has described variable levels of evidence for MODY susceptibility genes [14][15][16] were found only in mutation carriers of the 'consistent' genes, but not for the other genes. In participants without diabetes diagnosis, significantly higher proportion of family history and higher HbA1C…”

Section: Discussionmentioning

confidence: 98%

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Statistical evidence for high‐penetrance MODY‐causing genes in a large population‐based cohort

Billings

Shi

Resurreccion

et al. 2022

Endocrino Diabet & Metabol

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Aims Numerous genes have been proposed as causal for maturity‐onset diabetes of the young (MODY). Scoring systems to annotate mutation pathogenicity have been widely used; however, statistical evidence for being a highly penetrant MODY gene has not been well‐established. Methods Participants were from the UK Biobank with whole‐exome sequencing data, including 14,622 with and 185,509 without diagnosis of diabetes. Pathogenic/likely pathogenic (P/LP) mutations in 14 reported and 3 possible MODY genes were annotated using American College of Medical Genetics criteria. Evidence for being a high‐penetrant MODY gene used two statistical criteria: frequency of aggregate P/LP mutations in each gene are (1) significantly more common in participants with a diagnosis of diabetes than without using the SKAT‐O (p < .05) and (2) lower than the maximum credible frequency in the general population. Results Among the 17 genes, 6 (GCK, HNF1A, HNF4A, NEUROD1, KCNJ11 and HNF1B) met both criteria, 7 (ABCC8, KLF11, RFX6, PCBD1, WFS1, INS and PDX1) met only one criterion, and the remaining 4 (CEL, BLK, APPL1 and PAX4) failed both criteria, and were classified as ‘consistent’, ‘inconclusive’ and ‘inconsistent’ for being highly penetrant diabetes genes, respectively. Diabetes participants with mutations in the ‘consistent’ genes had clinical presentations that were most consistent with MODY. In contrast, the ‘inconclusive’ and ‘inconsistent’ genes did not differ clinically from non‐carriers in diabetes‐related characteristics. Conclusions Data from a large population‐based study provided novel statistical evidence to identify 6 MODY genes as consistent with being highly penetrant. These results have potential implications for interpreting genetic testing results and clinical diagnosis of MODY.

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Section: Discussionsupporting

confidence: 55%

“…It is notable that our findings using statistical method help underscore some of the prior evidence on the causality of MODY candidate genes and question others. Prior evidence has described variable levels of evidence for MODY susceptibility genes [14][15][16] were found only in mutation carriers of the 'consistent' genes, but not for the other genes. In participants without diabetes diagnosis, significantly higher proportion of family history and higher HbA1C…”

Section: Discussionmentioning

confidence: 98%

Statistical evidence for high‐penetrance MODY‐causing genes in a large population‐based cohort

Billings

Shi

Resurreccion

et al. 2022

Endocrino Diabet & Metabol

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“…Diabetes mellitus prevailed in 60% of the patients' families. Aside from blood glucose, there were no signi cant differences in MODY13 patients' sex, ethnicity, blood pressure, C-peptide, FT4, or insulin-related antibodies when versus KCNJ11 mutation-associated neonatal diabetes mellitus 16,[23][24][25] .…”

Section: Discussionmentioning

confidence: 86%

A synonymous variant in KCNJ11 leading to MODY13: a case report and literature review

Chen

Piao

Sang

2023

Preprint

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137words Background: MODY13 (Maturity-onset diabetes of the young, type 13) is monogenic diabetes associated with the KCNJ11 mutation rarely reported to date. A patient with c.843C>T(p.L281=) in the KCNJ11 gene is reported only in a Chinese patient with congenital hyperinsulinemia. There is no patient diagnosed with MODY13 carrying a synonymous heterozygous variant in the KCNJ11 reported till now. Method: We followed a 9-year-old boy presenting ketosis and diagnosed with MODY13. Whole-exome sequencing (WES) and Sanger validation were performed on the proband and his parents, respectively. Then bioinformatics software was used to predict the RNA structure and protein function. Result: The clinical characteristics and genetic traits of a 9-year-old boy with MODY13 are described in this study. WES revealed the synonymous heterozygous variant c.843C>T (p.L281=) in the KCNJ11 exon 1 in this patient, which prompted the opposite phenotype previously described. The patient and his mother who carries c.843C>T have morphologically comparable RNA structures of KCNJ11 which is completely separated from his mother. Conclusion: A c.843C>T (p.L281=) variant in the KCNJ11 gene contributes to MODY13. In clinical practice, WES should be applied to diagnose hyperglycemia in patients without characteristic clinical symptoms of diabetes to improve prognosis.

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“…In maturity-onset diabetes of the youth (MODY), several studies demonstrated some NEUROD1 candidate mutations, including NEUROD1 p.Pro197His, p.Asp202Glu, p.Leu157Arg, and p.Arg103Pro ( Ang et al, 2016 ; Aǧladioǧlu et al, 2016 ; Szopa et al, 2016 ; Horikawa et al, 2018 ; Demirci et al, 2021 ). Recently, another heterozygous mutation, NEUROD1 p.Met114Leu (c.340A > C), was reported in an Italian patient with MODY6 ( Brodosi et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of gene mutations associated with type 1 diabetes by next-generation sequencing in affected Palestinian families

Bawatneh,

Darwish,

Eideh

et al. 2024

Front. Genet.

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Introduction: Diabetes Mellitus is a group of metabolic disorders characterized by hyperglycemia secondary to insulin resistance or deficiency. It is considered a major health problem worldwide. T1DM is a result of a combination of genetics, epigenetics, and environmental factors. Several genes have been associated with T1DM, including HLA, INS, CTLA4, and PTPN22. However, none of these findings have been based on linkage analysis because it is rare to find families with several diabetic individuals. Two Palestinian families with several afflicted members with variations in the mode of inheritance were identified and selected for this study. This study aimed to identify the putative causative gene(s) responsible for T1DM development in these families to improve our understanding of the molecular genetics of the disease.Methods: One afflicted member from each family was selected for Whole-Exome Sequencing. Data were mapped to the reference of the human genome, and the resulting VCF file data were filtered. The variants with the highest phenotype correlation score were checked by Sanger sequencing for all family members. The confirmed variants were analyzed in silico by bioinformatics tools.Results: In one family, the IGF1R p.V579F variant, which follows autosomal dominant inheritance, was confirmed and segregated in the family. In another family, the NEUROD1 p.P197H variant, which follows autosomal recessive inheritance, was positively confirmed and segregated.Conclusion:IGF1R p.V579F and NEUROD1 p.P197H variants were associated with T1DM development in the two inflicted families. Further analysis and functional assays will be performed, including the generation of mutant model cell systems, to unravel their specific molecular mechanism in the disease development.

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Monogenic Childhood Diabetes: Dissecting Clinical Heterogeneity by Next-Generation Sequencing in Maturity-Onset Diabetes of the Young

Cited by 14 publications

References 80 publications

Statistical evidence for high‐penetrance MODY‐causing genes in a large population‐based cohort

Statistical evidence for high‐penetrance MODY‐causing genes in a large population‐based cohort

A synonymous variant in KCNJ11 leading to MODY13: a case report and literature review

Identification of gene mutations associated with type 1 diabetes by next-generation sequencing in affected Palestinian families

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