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

Abstract

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.

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

“…In the remaining, the variant arose de novo in 73.6% (28/38). Inherited mutations were found in 10 cases, of which maternally expressed [ 8 , 11 , 12 , 15 , 27 ] and paternally expressed [ 8 , 16 ] each account for 50%. So, GATA6 can be a de novo mutation or family inheritance, most are the former.…”

“…Intriguingly, carriers without pancreatic dysfunction and/or developmental defect occurred within maternal inheritance families (4/5), three of them were parents [ 11 , 12 , 15 , 27 ] and the remaining was younger brother [ 12 ]. Four were adult-onset diabetes [ 8 , 16 ] and one was childhood-onset diabetes [ 8 ] mellitus in paternal inherited families. No significant differences were found between maternally and paternally inheritance in other abnormalities.…”

Functional Genomic Screening in Human Pluripotent Stem Cells Reveals New Roadblocks in Early Pancreatic Endoderm Formation

“…Hence, albeit DSC2 was not essential for endoderm and pancreatic progenitor formation, perturbations in its expression and function might perturb the gene regulatory network involved in endodermal organ formation. The loss of DSC2 also resulted in a significant reduction in GATA6 expression at the endoderm stage, a marker vital for endoderm induction [6] that had been associated with the development of diabetes [49], pancreatic insufficiency, and congenital heart disease [50], and which plays a vital role in insulin production in adult β-cells [51]. Although pancreatic disorders or diabetes are not recognized characteristic features of patients with DSC2 mutations, a case of nonautoimmune diabetes diagnosed as type 2 diabetes was reported in one of the few described patients with biallelic DSC2 deficiency [44].…”

Clinical characteristics and genetic analysis of a child with specific type of diabetes mellitus caused by missense mutation of <italic>GATA6</italic> gene

“…人类 GATA6 基因位于染色体18q11.2，包含7个外显子，编码595个氨基酸，主要表达于心脏、胰腺等中、内胚层来源的组织中。现有证据显示， GATA6 变异患者的变异位点广泛，并可导致胰腺发育不全、先天性心脏病、消化系统发育障碍、神经认知异常，以及糖尿病、甲状腺功能减退、垂体发育不良、性腺功能减退等内分泌系统疾病，临床表现谱较广 ［ 5 - 9 ］ 。然而，其基因型与临床表型无明确相关性 ［ 10 ］ 。…”