Neonatal diabetes mellitus due to a novel mutation in the <i>GATA6</i> gene accompanying renal dysfunction: A case report

Tuhan, Hale; Çatlı, Gönül; Anık, Ahmet; Özmen, Derya; Türkmen, Mehmet; Böber, Ece; Abacı, Ayhan

doi:10.1002/ajmg.a.36984

Cited by 7 publications

(5 citation statements)

References 13 publications

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“…Several distinct GATA6 mutations have been described in the literature, without direct genotype-phenotype correlation. Our patient possessed a nonsense GATA6 mutation (c.1242C>A, p.C414*), previously described in a case report in which a patient had pancreatic agenesis, neonatal diabetes, renal dysfunction, atrial septal defect, ventricular septal defect (VSD), pulmonary stenosis, and patent ductus arteriosus (11). In contrast, our patient had significantly less severe pancreatic manifestations and lacked any known renal dysfunction.…”

Section: Discussionmentioning

confidence: 64%

A Nonsense GATA6 Mutation Explains History of Congenital Heart Defects and 10 Years of Poorly-Controlled Diabetes Lacking DKA in a Non-Obese 30 Year-Old Incidentally Found to Have Pancreatic Hypoplasia

Miles

Cowan

Jackson

2020

AACE Clinical Case Reports

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Objective: To report a case of diabetes mellitus (DM) associated with partial pancreatic agenesis and congenital heart disease (CHD) in a patient found to have a nonsense mutation of the GATA6 gene. Methods: We present the imaging, laboratory, and genetic findings, and describe the clinical course of a patient with an atypical presentation of DM as well as CHD, who was found to have partial pancreatic agenesis on computed tomography (CT) imaging. Genetic testing was performed to identify monogenic DM. Results: A 30-year-old nonobese female with a waxing and waning pattern of insulin-dependent DM diagnosed at the age of 20 was found to have partial pancreatic agenesis on CT scan. It was unclear whether the patient was experiencing undetected hyperglycemia prior to initial diagnosis of DM. She had no history of diabetic ketoacidosis (DKA) despite poorly-controlled diabetes and years without insulin treatment. The patient also had congenital tricuspid atresia, ventricular septal defect, and transposition of the great vessels with surgical correction in childhood. Partial pancreatic agenesis and CHD with atypical DM prompted genetic testing for monogenic DM, and a nonsense mutation of the GATA6 (c.1242C>A, p.C414*) gene was found. Conclusion: GATA6 mutations are associated with a broad spectrum of diabetic phenotypes, pancreatic agenesis, and a variety of CHDs. This case highlights the importance of considering monogenic diabetes in young, nonobese patients with diabetes, particularly with negative pancreatic antibodies and no history of DKA. Further, this case demonstrates the importance of testing for GATA6 mutations in any young patient with diabetes and CHD.

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Section: Discussionmentioning

confidence: 64%

A Nonsense GATA6 Mutation Explains History of Congenital Heart Defects and 10 Years of Poorly-Controlled Diabetes Lacking DKA in a Non-Obese 30 Year-Old Incidentally Found to Have Pancreatic Hypoplasia

Miles

Cowan

Jackson

2020

AACE Clinical Case Reports

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“…Four mutations were found in more than one independent proband (c. 1242C > A [ 14 , 18 ], c. 1366C > T [ 9 , 19 , 26 ], c. 1367G > A [ 9 , 20 ], c. 1504_1505del [ 11 , 13 ]) and one of these, c. 1366C > T p. (Arg456Cys) was even found in four independent probands. It is located in the C-zinc finger domain of the protein, essential for modifying the DNA-bind function by active with GATA6 protein.…”

Section: Resultsmentioning

confidence: 99%

Monogenic Diabetes with GATA6 Mutations: Characterization of a Novel Family and a Comprehensive Analysis of the GATA6 Clinical and Genetics Traits

et al. 2023

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Monogenic diabetes caused by GATA6 mutations were almost described as neonatal diabetes, and the phenotypic spectrum has expanded since then. Our study underscores the broad phenotypic spectrum by reporting a de novo GATA6 mutation in a family. Furthermore, we reviewed related literature to summarize the clinical and genetic characteristics of monogenic diabetes with GATA6 mutations (n = 39) in order to improve clinicians’ understanding of the disease. We conclude that the GATA6 missense mutation (c. 749G > T, p. Gly250Val) is not reported presently, characterized by adult-onset diabetes with pancreatic dysplasia and located in transcriptional activation region. Carries with GATA6 mutations (n = 55) have a variable spectrum of diabetes, ranging from neonatal (72.7%), childhood-onset (20%) to adults-onset (7.5%). 83.5% of patients with abnormal pancreatic development. Heart and hepatobillary defects are the most common abnormalities of extrapancreatic features. Most mutations with GATA6 are loss of function (LOF, 71.8%) and located in functional region. Functional studies mostly support loss-of-function as the pathophysiological mechanism. In conclusion, there are various types of diabetes with GATA6 mutations, which can also occur in adult diabetes. Phenotypic defects with GATA6 mutations are most frequently malformations of pancreas and heart. This highlights the importance of comprehensive clinical evaluation of identified carriers to evaluate their full phenotypic spectrum.

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“…Permanent neonatal diabetes is most commonly due to mutations in KCNJ11 , ABCC8 , INS and GCK (3). Neonatal diabetes specifically related to pancreatic agenesis arises from mutations in multiple genes including PDX1 , PTF1A , HNF1B , EIF2AK3 , RFX6 and GATA6 (4). Only the latter gene is currently implicated in the combined phenotype of pancreatic agenesis and congenital heart disease (5) and enabled a successful single-gene approach in the present case using Sanger sequencing.…”

Section: Discussionmentioning

confidence: 99%

“…Dysmorphic facial features as observed in this case have not been described. There has been one report of proteinuria in an infant with a GATA6 -truncating variant (4) and another child with a GATA6 deletion and structural renal abnormalities (9). However, to our knowledge, our case is the only report detailing renal histology in an individual with a GATA6 mutation and proteinuria.…”

Section: Discussionmentioning

confidence: 99%

Familial GATA6 mutation causing variably expressed diabetes mellitus and cardiac and renal abnormalities

Moore

Poplawski

et al. 2019

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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Summary A 26-year-old man presented with a combination of permanent neonatal diabetes due to pancreatic aplasia, complex congenital heart disease, central hypogonadism and growth hormone deficiency, structural renal abnormalities with proteinuria, umbilical hernia, neurocognitive impairment and dysmorphic features. His older brother had diabetes mellitus due to pancreatic hypoplasia, complex congenital heart disease, hypospadias and umbilical hernia. Their father had an atrial septal defect, umbilical hernia and diabetes mellitus diagnosed incidentally in adulthood on employment screening. The proband’s paternal grandmother had a congenital heart defect. Genetic testing of the proband revealed a novel heterozygous missense variant (Chr18:g.19761441T>C, c.1330T>C, p.Cys444Arg) in exon 4 of GATA6, which is class 5 (pathogenic) using American College of Medical Genetics and Genomics guidelines and is likely to account for his multisystem disorder. The same variant was detected in his brother and father, but not his paternal grandmother. This novel variant of GATA6 likely occurred de novo in the father with autosomal dominant inheritance in the proband and his brother. The case is exceptional as very few families with monogenic diabetes due to GATA6 mutations have been reported to date and we describe a new link between GATA6 and renal pathology. Learning points: Monogenic diabetes should be suspected in patients presenting with syndromic features, multisystem congenital disease, neonatal-onset diabetes and/or a suggestive family history. Recognition and identification of genetic diabetes may improve patient understanding and empowerment and allow for better tailored management. Identification of a genetic disorder may have important implications for family planning.

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Neonatal diabetes mellitus due to a novel mutation in the GATA6 gene accompanying renal dysfunction: A case report

Cited by 7 publications

References 13 publications

A Nonsense GATA6 Mutation Explains History of Congenital Heart Defects and 10 Years of Poorly-Controlled Diabetes Lacking DKA in a Non-Obese 30 Year-Old Incidentally Found to Have Pancreatic Hypoplasia

A Nonsense GATA6 Mutation Explains History of Congenital Heart Defects and 10 Years of Poorly-Controlled Diabetes Lacking DKA in a Non-Obese 30 Year-Old Incidentally Found to Have Pancreatic Hypoplasia

Monogenic Diabetes with GATA6 Mutations: Characterization of a Novel Family and a Comprehensive Analysis of the GATA6 Clinical and Genetics Traits

Familial GATA6 mutation causing variably expressed diabetes mellitus and cardiac and renal abnormalities

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