Novel pathogenic GATA6 variant associated with congenital heart disease, diabetes mellitus and necrotizing enterocolitis.
Novel pathogenic GATA6 variant associated with congenital heart disease, diabetes mellitus and necrotizing enterocolitis.
复制标题
DOI：
10.1038/s41390-023-02811-y
复制
发表时间：
2023-09
影响因子：
3.6
通讯作者：
J. Yasuhara;Sathiya N Manivannan;Uddalak Majumdar;David M. Gordon;Patrick J. Lawrence;Mona Aljuhani;K. Myers;C. Stiver;Amee M. Bigelow;M. Galantowicz;Hiroyuki Yamagishi;Kim L McBride;Peter White;V. Garg
中科院分区：
文献类型：
--
作者：
J. Yasuhara;Sathiya N Manivannan;Uddalak Majumdar;David M. Gordon;Patrick J. Lawrence;Mona Aljuhani;K. Myers;C. Stiver;Amee M. Bigelow;M. Galantowicz;Hiroyuki Yamagishi;Kim L McBride;Peter White;V. Garg
背景致病性 GATA6 变异与先天性心脏病 (CHD) 和一系列心外异常有关，包括胰腺发育不全、先天性膈疝和发育迟缓。然而，人类致病性GATA6变异的全面基因型-表型相关性仍有待完全了解。方法对一个有四名成员患有CHD的家庭进行外显子组测序。使用免疫荧光、蛋白质印迹和双荧光素酶报告基因测定对 GATA6 变体进行体外功能分析。结果 GATA6 中的一种新型杂合错义变体（c.1403 G > A；p.Cys468Tyr）与 CHD 家族中受影响的成员分离，其中包括 3 个患有持续性动脉干的成员。此外，一名成员患有儿童期发病的糖尿病（DM），另一名成员患有坏死性小肠结肠炎（NEC）并伴有肠穿孔。 p.Cys468Tyr 变体位于外显子 4 编码的 C 端锌指结构域中。该突变蛋白表现出异常的核定位模式，伴有蛋白质聚集和转录活性降低。结论我们报告了一种与 CHD、DM 和 NEC 肠穿孔相关的新型家族性 GATA6 可能致病性变体。这些发现扩大了病理性 GATA6 变异的表型谱，包括肠道异常。ImpactExome 测序发现了一种新的杂合 GATA6 变异 (p.Cys468Tyr)，该变异在患有 CHD 的家族中分离，包括持续性动脉干、房间隔缺损和二叶式主动脉瓣。此外，受影响的成员表现出心外表现，包括儿童期发病的糖尿病，以及独特的，出生后四天内出现肠穿孔的坏死性小肠结肠炎。体外功能测定表明，GATA6p.Cys468Tyr 变异导致细胞定位缺陷和反式激活活性降低。这项工作支持 GATA6 作为 CHD 致病基因的重要性，并扩大了致病性 GATA6 变异的表型谱，强调新生儿肠穿孔是一种新的心外表型。
BackgroundPathogenicGATA6variants have been associated with congenital heart disease (CHD) and a spectrum of extracardiac abnormalities, including pancreatic agenesis, congenital diaphragmatic hernia, and developmental delay. However, the comprehensive genotype-phenotype correlation of pathogenicGATA6variation in humans remains to be fully understood.MethodsExome sequencing was performed in a family where four members had CHD. In vitro functional analysis of theGATA6variant was performed using immunofluorescence, western blot, and dual-luciferase reporter assay.ResultsA novel, heterozygous missense variant inGATA6(c.1403 G > A; p.Cys468Tyr) segregated with affected members in a family with CHD, including three with persistent truncus arteriosus. In addition, one member had childhood onset diabetes mellitus (DM), and another had necrotizing enterocolitis (NEC) with intestinal perforation. The p.Cys468Tyr variant was located in the c-terminal zinc finger domain encoded by exon 4. The mutant protein demonstrated an abnormal nuclear localization pattern with protein aggregation and decreased transcriptional activity.ConclusionsWe report a novel, familialGATA6likely pathogenic variant associated with CHD, DM, and NEC with intestinal perforation. These findings expand the phenotypic spectrum of pathologicGATA6variation to include intestinal abnormalities.ImpactExome sequencing identified a novel heterozygousGATA6variant (p.Cys468Tyr) that segregated in a family with CHD including persistent truncus arteriosus, atrial septal defects and bicuspid aortic valve. Additionally, affected members displayed extracardiac findings including childhood-onset diabetes mellitus, and uniquely, necrotizing enterocolitis with intestinal perforation in the first four days of life.In vitro functional assays demonstrated thatGATA6p.Cys468Tyr variant leads to cellular localization defects and decreased transactivation activity.This work supports the importance ofGATA6as a causative gene for CHD and expands the phenotypic spectrum of pathogenicGATA6variation, highlighting neonatal intestinal perforation as a novel extracardiac phenotype.