Three unreported glucokinase (GCK) missense mutations detected in the screening of thirty-two Brazilian kindreds for GCK and HNF1A-MODY

Weinert, Letícia Schwerz; Silveiro, Sandra Pinho; Giuffrida, Fernando de Mello Almada; Cunha, Vivian Trein; Bulcão, Caroline; Calliari, Luís Eduardo; Manna, Thaís Della; Kunii, Ilda S.; Dotto, Renata Pires; Silva, Magnus R. Dias da; Reis, André

doi:10.1016/j.diabres.2014.08.006

Cited by 9 publications

(8 citation statements)

References 16 publications

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“…(58) There have been multiple small studies of Brazilian populations, but they are generally underpowered and have conflicting results. (59–61) A small Mexican cohort has been studied, but no follow up studies have been performed to validate any findings. (62) It is unclear why MODY epidemiological studies have not been pursued in these ethnic populations.…”

Section: Mody Epidemiology Studiesmentioning

confidence: 99%

Undiagnosed MODY: Time for Action

2015

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Maturity-Onset Diabetes of the Young (MODY) is a monogenic form of diabetes that accounts for at least 1% of all cases of diabetes mellitus. MODY classically presents as non-insulin requiring diabetes in lean individuals younger than 25 with evidence of autosomal dominant inheritance, but these criteria do not capture all cases and can also overlap with other diabetes types. Genetic diagnosis of MODY is important for selecting the right treatment, yet ~95% of MODY cases in the U.S. are misdiagnosed. MODY prevalence and characteristics have been well-studied in some populations, such as the UK and Norway, while other ethnicities, like African and Latino, need much more study. Emerging next-generation sequencing methods are making more widespread study and clinical diagnosis increasingly feasible. This review will cover the current epidemiological studies of MODY and barriers and opportunities for moving toward a goal of access to an appropriate diagnosis for all affected individuals.

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Section: Mody Epidemiology Studiesmentioning

confidence: 99%

Undiagnosed MODY: Time for Action

2015

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“…These data allow us to estimate the number of MODY cases in Brazil as approximately 140 000 to 280 000. However, until 2016, around 200 subjects of about 50 Brazilian families diagnosed with the 2 most common subtypes of MODY ( GCK and HNF1A ) have been described . Hence, MODY cases are clearly underestimated in Brazil.…”

Section: Introductionmentioning

confidence: 99%

“…However, until 2016, around 200 subjects of about 50 Brazilian families diagnosed with the 2 most common subtypes of MODY (GCK and HNF1A) have been described. [5][6][7][8][9][10][11][12][13][14][15][16][17][18] Hence, MODY cases are clearly underestimated in Brazil. Besides that, there is a great racial diversity in Brazilian people, contributing to a wide genetic background, an important difference from countries with more homogeneous population.…”

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confidence: 99%

Clinical application of ACMG‐AMP guidelines in HNF1A and GCK variants in a cohort of MODY families

et al. 2017

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Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. GCK -MODY and HNF1A -MODY are the prevalent subtypes. Currently, there is growing concern regarding the correct interpretation of molecular genetic findings. The American College of Medical Genetics and Genomics (ACMG) updated guidelines to interpret and classify molecular variants. This study aimed to determine the prevalence of MODY ( GCK / HNF1A ) in a large cohort of Brazilian families, to report variants related to phenotype, and to classify them according to ACMG guidelines. One hundred and nine probands were investigated, 45% with clinical suspicion of GCK -MODY and 55% with suspicion of HNF1A -MODY. Twenty-five different variants were identified in GCK gene (30 probands-61% of positivity), and 7 variants in HNF1A (10 probands-17% of positivity). Fourteen of them were novel (12- GCK /2- HNF1A ). ACMG guidelines were able to classify a large portion of variants as pathogenic (36%- GCK /86%- HNF1A ) and likely pathogenic (44%- GCK /14%- HNF1A ), with 16% (5/32) as uncertain significance. This allows us to determine the pathogenicity classification more efficiently, and also reinforces the suspected associations with the phenotype among novel variants.

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“…These consisted of 16 missense, two nonsense, one frameshift, and one synonymous variant. Thirteen variants have already been reported in MODY patients, namely GCK c.130G>A [15], GCK c.386G>A [16], GCK c.544G>A [17], GCK c.556C>T [18], GCK c.698G>A [19], GCK c.757G>C [20], GCK c.1099G>A [21], GCK c.1268T>A [22], HNF1A c.425C>T [23], HNF1A c.475C>T [24], HNF1A c.511C>T [23], HNF1A c.521C>T [25], and HNF1A c.607C>A [26].…”

Section: Resultsmentioning

confidence: 99%

“…The 23 identified mutations consisted of 20 unique mutations and three recurrent mutations (i.e., occurring in more than one family). Of these 20 different mutations, 13 have already been reported in MODY [15][16][17][18][19][20][21][22][23][24][25][26]. The remaining seven 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) have not previously been reported, and are therefore novel mutations.…”

Section: Discussionmentioning

confidence: 99%

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

Alvelos

Gonçalves

Coutinho

et al. 2020

JCM

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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.

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Three unreported glucokinase (GCK) missense mutations detected in the screening of thirty-two Brazilian kindreds for GCK and HNF1A-MODY

Cited by 9 publications

References 16 publications

Undiagnosed MODY: Time for Action

Undiagnosed MODY: Time for Action

Clinical application of ACMG‐AMP guidelines in HNF1A and GCK variants in a cohort of MODY families

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

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