Unexpected finding of a whole HNF1B gene deletion during the screening of rare MODY types in a series of Brazilian patients negative for GCK and HNF1A mutations

Dotto, Renata Pires; Giuffrida, Fernando de Mello Almada; Franco, Luciana Ferreira; Mathez, Andréia Latanza Gomes; Weinert, Letícia Schwerz; Silveiro, Sandra Pinho; Joao, R.; Reis, André; Silva, Magnus R. Dias da

doi:10.1016/j.diabres.2016.04.035

Cited by 9 publications

(6 citation statements)

References 19 publications

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“…We detected 2 out of 28 cases (7%). Previously, we described an isolated case of HNF1B mutation in a Brazilian patient with familial DM and hypomagnesemia recruited due to suspicion of MODY (15). The prevalence of mutations in HNF1B is variable, mainly due to the high degree of clinical heterogeneity and various recruitment strategies regarding age range and distinct phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…Analysis of the 9 exons of HNF1B and the promoter region was performed by DNA amplification through polymerase chain reaction followed by Sanger sequencing using a Big Dye Terminator TM Cycle Sequencing Ready Reaction Kit and ABI PRISM 3130 xl Genetic Analyzer (Applied Biosystems, Foster City, CA, USA), as previously described (15). Primers used are detailed in Supplementary Table 1.…”

Section: Genetic Analysesmentioning

confidence: 99%

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Searching for mutations in the HNF1B gene in a Brazilian cohort with renal cysts and hyperglycemia

Dotto¹,

Santana²,

Lindsey³

et al. 2019

Archives of Endocrinology and Metabolism

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Objective To verify the presence of variants in HNF1B in a sample of the Brazilian population selected according to the presence of renal cysts associated with hyperglycemia. Subjects and methods We evaluated 28 unrelated patients with clinical suspicion of HNF1B mutation because of the concomitant presence of diabetes mellitus (DM) or prediabetes and renal cysts. Genotyping was accomplished using Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA). In positive cases, available relatives were recruited. Results We found two patients with HNF1B mutations. The first presented the variant p.Pro328Leufs*48(c.983delC) and had DM, renal cysts, and hypomagnesemia. The second presented a heterozygous whole gene deletion in HNF1B, DM, renal cysts, body and tail pancreatic agenesis, and hypomagnesemia; this alteration was also found in his two siblings and his father. Conclusion The recruitment of suspected cases of HNF1B gene mutations in Brazilians due to hyperglycemia and renal cysts presents two positive cases. Our cases contribute to the annotation of clinical and biochemical phenotypes of this rare form of maturity-onset diabetes of the young (MODY).

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Section: Discussionmentioning

confidence: 99%

Section: Genetic Analysesmentioning

confidence: 99%

Searching for mutations in the HNF1B gene in a Brazilian cohort with renal cysts and hyperglycemia

Dotto¹,

Santana²,

Lindsey³

et al. 2019

Archives of Endocrinology and Metabolism

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“…Like his brother he has also presented with hematuria for several years and persistent proteinuria (around 0.85 g/L), renal cysts at ultrasound, and stable creatinine clearance over the last few years (ranging from 90 to 110 mL/min). One hypothesis for explaining the etiology of hyperglycemia with renal alterations, especially renal cysts, could be an HNF1B mutation, which has also been tested with negative results, consequently excluding this MODY subtype also in his twin brother (4,23).…”

Section: Discussionmentioning

confidence: 99%

“…Pathogenicity of mutations was assessed by the American College of Medical Genetics and Genomics (ACMG) guidelines (3). HNF1B genotyping was performed with previously described methods (4). Hemoglobin A1c (HbA1c) was analyzed by High-Performance Liquid Chromatography (HPLC).…”

Section: Methodsmentioning

confidence: 99%

More than kin, less than kind: one family and the many faces of diabetes in youth

Franco

Peixoto-Barbosa

Dotto

et al. 2017

Arch. Endocrinol. Metab.

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SUMMARYIdentification of the correct etiology of diabetes brings important implications for clinical management. In this report, we describe a case of a 4-year old asymptomatic girl with diabetes since age 2, along with several individuals in her family with different etiologies for hyperglycemia identified in youth. Genetic analyses were made by Sanger sequencing, laboratory measurements included HbA1c, lipid profile, fasting C-peptide, pancreatic auto-antibodies (glutamic acid decarboxylase [GAD], Islet Antigen 2 [IA-2], and anti-insulin). We found a Gly178Ala substitution in exon 5 of GCK gene in three individuals co-segregating with diabetes, and type 1 diabetes was identified in two other individuals based on clinical and laboratory data. One individual with previous gestational diabetes and other with prediabetes were also described. We discuss difficulties in defining etiology of hyperglycemia in youth in clinical practice, especially monogenic forms of diabetes, in spite of the availability of several genetic, laboratory, and clinical tools. Arch Endocrinol Metab. 2017;61(6):637-42

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“…Since the breakthroughs of molecular genetic testing technology from 1990s, relevant studies have recognized that MODY comprises several different clinical syndromes of familial diabetes resulting from specific molecular defects (3). There are 14 genes that have been proven related to MODY, including HNF1A, GCK, HNF4A, HNF1B, ABCC8, and so on (4). In Europe, MODY accounted for 1-2% of the total diabetes population (5), but the exact prevalence of MODY all over the world was not known.…”

Section: Introductionmentioning

confidence: 99%

MODY2 in Asia: analysis of GCK mutations and clinical characteristics

Zhou¹,

Wang²,

Wu³

et al. 2020

Endocrine Connections

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Aims Heterozygous inactivating mutations in the GCK gene cause the familial, mild fasting hyperglycaemia named MODY2. Many patients with MODY2 in Asia have delayed timely treatment because they did not receive the correct diagnosis. This study aims to analyze the clinical characteristics and GCK mutations in Asian MODY2. Methods We have collected 110 Asian patients with MODY2 from the PubMed, Embase, Medline, Web of Science, CNKI, and Wanfang with the following search terms: ‘maturity-onset diabetes of the young’ OR ‘MODY’ OR ‘maturity-onset diabetes of the young type 2’ OR ‘MODY2’ OR ‘GCK-DM’ OR ‘GCK-MODY’. Both mutations of GCK and clinical characteristics of MODY2 were analyzed. Results There were 96 different mutations that occurred in coding regions and non-coding regions. Exon 5 and 7 were the most common location in coding regions and missense was the primary mutation type. The proportion of probands younger than 25 was 81.8%, and 81.4% of the probands had family history of hyperglycaemia. Ninety percent and 93% of Asian MODY2 probands exhibited mild elevation in FPG (5.4–8.3 mmol/L) and HbA1c (5.6–7.6%), respectively. Conclusions In most Asian patients, MODY2 occurred due to GCK mutation in coding regions, and exon 5 and 7 were the most common locations. FPG, HbA1c, and familial diabetes were important reference indicators for diagnosing MODY2. Altogether, the study indicates that for the young onset of diabetes with mild elevated blood glucose and HbA1c and family history of hyperglycaemia, molecular genetic testing is suggested in order to differentiate MODY2 from other types of diabetes earlier.

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Unexpected finding of a whole HNF1B gene deletion during the screening of rare MODY types in a series of Brazilian patients negative for GCK and HNF1A mutations

Cited by 9 publications

References 19 publications

Searching for mutations in the HNF1B gene in a Brazilian cohort with renal cysts and hyperglycemia

Searching for mutations in the HNF1B gene in a Brazilian cohort with renal cysts and hyperglycemia

More than kin, less than kind: one family and the many faces of diabetes in youth

MODY2 in Asia: analysis of GCK mutations and clinical characteristics

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