Maturity-onset diabetes of the young (MODY) in Brazil: Establishment of a national registry and appraisal of available genetic and clinical data

Giuffrida, Fernando de Mello Almada; Moises, Regina Celia Mello Santiago; Weinert, Letícia Schwerz; Calliari, Luís Eduardo; Manna, Thaís Della; Dotto, Renata Pires; Franco, Luciana Ferreira; Caetano, Lílian Araújo; Teles, Milena Gurgel; Lima, Renata Andrade; Alves, Crésio; Dib, Sérgio Atala; Silveiro, Sandra Pinho; Silva, Magnus R. Dias da; Reis, André

doi:10.1016/j.diabres.2016.10.017

Cited by 21 publications

(19 citation statements)

References 58 publications

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“…The frequency of GCK mutations in this study was slightly higher than previously reported for most populations (42.4 to 61%), including Brazilians (21-23). We found mutations in HNF1A, the most common gene for non-GCK MDM, in 18.5%, which was much like the data obtained by Santana and coworkers in the Brazilian population but lower than reported in other populations (16)(17)(18)(19)24). Therefore, the clinical criteria for the selection of patients for GCK testing seem to be adequate in most populations, including ours.…”

Section: Bsupporting

confidence: 83%

MODY probability calculator for GCK and HNF1A screening in a multiethnic background population

Tarantino¹,

Abreu²,

Fonseca³

et al. 2019

Archives of Endocrinology and Metabolism

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Objective: We aimed to identify the frequency of monogenic diabetes, which is poorly studied in multiethnic populations, due to GCK or HNF1A mutations in patients with suggestive clinical characteristics from the Brazilian population, as well as investigate if the MODY probability calculator (MPC) could help patients with their selection. Subjects and methods: Inclusion criteria were patients with DM diagnosed before 35 years; body mass index < 30 kg/m 2 ; negative autoantibodies; and family history of DM in two or more generations. We sequenced HNF1A in 27 patients and GCK in seven subjects with asymptomatic mild fasting hyperglycemia. In addition, we calculated MODY probability with MPC. Results: We identified 11 mutations in 34 patients (32.3%). We found three novel mutations. In the GCK group, six cases had mutations (85.7%), and their MODY probability on MPC was higher than 50%. In the HNF1A group, five of 27 individuals had mutations (18.5%). The MPC was higher than 75% in 11 subjects (including all five cases with HNF1A mutations). Conclusion: Approximately one third of the studied patients have GCK or HNF1A mutations. Inclusion criteria included efficiency in detecting patients with GCK mutations but not for HNF1A mutations (< 20%). MPC was helpful in narrowing the number of candidates for HNF1A screening.

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Section: Bsupporting

confidence: 83%

MODY probability calculator for GCK and HNF1A screening in a multiethnic background population

Tarantino¹,

Abreu²,

Fonseca³

et al. 2019

Archives of Endocrinology and Metabolism

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“…We identified a higher prevalence of GCK ‐MODY (28%—30/109), in contrast to 9% (10/109) of HNF1A ‐MODY, remaining 63% (69/109) of negative cases. These numbers are similar to those recently reported in a national registry of MODY cases in Brazil . Giuffrida et al gathered more clinical details of already published MODY Brazilian cases in the last few years.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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“…However, only a small proportion of MODY cases were caused by GCK‐MODY in Korea (2.5%) and China (1%) . Studies focused on adult patients have unequivocally shown that HNF1A/HNF4A‐MODY are two to four times more frequent than GCK‐MODY, which is more prevalent in children and adolescents . This is likely a direct consequence of selection criterium based also on IFG, asymptomatic children with IFG are usually referred to specialists, while asymptomatic adults with IFG are not.…”

Section: Discussionmentioning

confidence: 99%

Molecular diagnosis of maturity‐onset diabetes of the young in a cohort of Chinese children

Lin

Sheng

et al. 2020

Pediatr Diabetes

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Objective: The purpose of this study was to investigate the molecular basis of maturity-onset diabetes of the young (MODY) by whole-exome sequencing (WES) and estimate the frequency and describe the clinical characteristics of MODY in southern China. Methods: Genetic analysis was performed in 42 patients with MODY aged 1 month to 18 years among a cohort of 759 patients with diabetes, identified with the following four clinical criteria: age of diagnosis ≤18 years; negative pancreatic autoantibodies; family history of diabetes; or persistently detectable C-peptide; or diabetes associated with extrapancreatic features. GCK gene mutations were first screened by Sanger sequencing. GCK mutation-negative patients were further analyzed by WES. Results: Mutations were identified in 24 patients: 20 mutations in GCK, 1 in HNF4A, 1 in INS, 1 in ABCC8, and a 17q12 microdeletion. Four previously unpublished novel GCK mutations: c.1108G>C in exon 9, and c.1339C>T, c.1288_1290delCTG, and c.1340_1343delGGGGinsCTGGTCT in exon 10 were detected. WES identified a novel missense mutation c.311A>G in exon 3 in the INS gene, and copy number variation analysis detected a 1.4 Mb microdeletion in the long arm of the chromosome 17q12 region. Compared with mutation-negative subjects, the mutation-positive subjects had lower hemoglobin A1c and initial blood glucose levels. Conclusions: Most MODY cases in this study were due to GCK mutations, which is in contrast to previous reports in Chinese patients. Diabetes associated with extrapancreatic features should be a clinical criterion for MODY genetic analysis. Mutational analysis by WES provided a precise diagnosis of MODY subtypes. Moreover, WES can be useful for detecting large deletions in coding regions in addition to point mutations. K E Y W O R D S childhood, maturity-onset diabetes of the young, South China, whole-exome sequencing Aijing Xu and Yunting Lin contribute equally to this work.

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Maturity-onset diabetes of the young (MODY) in Brazil: Establishment of a national registry and appraisal of available genetic and clinical data

Cited by 21 publications

References 58 publications

MODY probability calculator for GCK and HNF1A screening in a multiethnic background population

MODY probability calculator for GCK and HNF1A screening in a multiethnic background population

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

Molecular diagnosis of maturity‐onset diabetes of the young in a cohort of Chinese children

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