When is it MODY? Challenges in the Interpretation of Sequence Variants in MODY Genes

Althari, Sara; Gloyn, Anna L.

doi:10.1900/rds.2015.12.330

Cited by 20 publications

(10 citation statements)

References 117 publications

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“…It is estimated to affect 2-5% of all diabetic cases, however this may be inaccurate or underestimated globally due to being undiagnosed or unclassifi ed as type 1 diabetes or type 2 diabetes because of overlapping clinical features [1]. It is often developed before the age 25 years and diabetes often runs in families from one generation to the next [2]. The result of the study disclosed in 1960, reported that mild, asymptomatic diabetes occurs in non-obese children, adolescents, and young adults of relatives of known diabetic patients.…”

Section: Introductionmentioning

confidence: 99%

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Maturity Onset Diabetes of the Young: A Rare Monogenic Form of Diabetes

Kallarackal¹

2019

Int J Clin Endocrinol Metab

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Diabetes Mellitus is a group of metabolic disorders associated with microvascular and macrovascular complications. The rapidly increasing prevalence and incidence of this disease is causing a major worldwide health problem. Maturity onset diabetes of the young (MODY) is a rare monogenic form of diabetes resulting from mutation in a single gene. There are 13 types of MODY genes identifi ed currently. The two main types of MODY is caused by mutations in the hepatocyte nuclear factor 1A and glycolytic enzyme glucokinase (GCK). Genetic testing is the gold standard for diagnosing MODY. It is essential to identify the MODY subtype to determine the management and treatment options.

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Section: Introductionmentioning

confidence: 99%

“…MODY2 and MODY3 are the most prevalent representing 20-70% of all MODY cases [6]. There are more genes that have been associated with MODY, however they are exceptionally rare having been reported once and detected in very few families [2]. [8].…”

Section: Introductionmentioning

confidence: 99%

Maturity Onset Diabetes of the Young: A Rare Monogenic Form of Diabetes

Kallarackal¹

2019

Int J Clin Endocrinol Metab

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“…Homozygous loss-of-function germline mutations are thought to be embryonically lethal (5). Establishing the pathogenicity of missense variants is challenging (6,7): hypomorphic variants in the heterozygous state may be dismissed as benign, but when inherited recessively, they may mimic loss-of-function heterozygous mutations (8).…”

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confidence: 99%

Homozygous Hypomorphic HNF1A Alleles Are a Novel Cause of Young-Onset Diabetes and Result in Sulfonylurea-Sensitive Diabetes

et al. 2020

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Heterozygous loss-of-function mutations in HNF1A cause maturity-onset diabetes of the young (MODY). Affected individuals can be treated with low-dose sulfonylureas. Individuals with homozygous HNF1A mutations causing MODY have not been reported. RESEARCH DESIGN AND METHODS We phenotyped a kindred with young-onset diabetes and performed molecular genetic testing, a mixed meal tolerance test, a sulfonylurea challenge, and in vitro assays to assess variant protein function. RESULTS A homozygous HNF1A variant (p.A251T) was identified in three insulin-treated family members diagnosed with diabetes before 20 years of age. Those with the homozygous variant had low hs-CRP levels (0.2-0.8 mg/L), and those tested demonstrated sensitivity to sulfonylurea given at a low dose, completely transitioning off insulin. In silico modeling predicted a variant of unknown significance; however, in vitro studies supported a modest reduction in transactivation potential (79% of that for the wild type; P < 0.05) in the absence of endogenous HNF1A. CONCLUSIONS Homozygous hypomorphic HNF1A variants are a cause of HNF1A-MODY. We thus expand the allelic spectrum of variants in dominant genes causing diabetes.

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“…Maturity onset diabetes of the young (MODY) is currently under‐recognized clinically, and may also be under‐recognized by molecular genetic analysis . Genetic testing for MODY is presently accomplished primarily using next generation sequencing (NGS) techniques . However, these techniques are historically unable to detect copy number variations (CNVs), defined as large‐scale deletions or duplications in genomic DNA.…”

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confidence: 99%

“…1 Genetic testing for MODY is presently accomplished primarily using next generation sequencing (NGS) techniques. 1,2,4 However, these techniques are historically unable to detect copy number variations (CNVs), defined as large-scale deletions or duplications in genomic DNA. We report here on a largescale heterozygous CNV in HNF4A causing MODY in an individual who initially tested negative for mutations by DNA sequencing alone.…”

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confidence: 99%