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GATA6 mutations: Characterization of two novel patients and a comprehensive overview of the GATA6 genotypic and phenotypic spectrum
Author(s) -
ŠkorićMilosavljević Doris,
Tjong Fleur V. Y.,
Barc Julien,
Backx Ad P. C. M.,
Clur SallyAnn B.,
SpaendonckZwarts Karin,
Oostra RoelofJan,
Lahrouchi Najim,
Beekman Leander,
Bökenkamp Regina,
BargeSchaapveld Daniela Q. C. M.,
Mulder Barbara J.,
Lodder Elisabeth M.,
Bezzina Connie R.,
Postma Alex V.
Publication year - 2019
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.61294
Subject(s) - gata6 , phenotype , genetics , truncus arteriosus , biology , genetic heterogeneity , penetrance , haploinsufficiency , mutation , medicine , pathology , heart disease , gene , tetralogy of fallot , transcription factor
The first human mutations in GATA6 were described in a cohort of patients with persistent truncus arteriosus, and the phenotypic spectrum has expanded since then. This study underscores the broad phenotypic spectrum by presenting two patients with de novo GATA6 mutations, both exhibiting complex cardiac defects, pancreatic, and other abnormalities. Furthermore, we provided a detailed overview of all published human genetic variation in/near GATA6 published to date and the associated phenotypes ( n = 78). We conclude that the most common phenotypes associated with a mutation in GATA6 were structural cardiac and pancreatic abnormalities, with a penetrance of 87 and 60%, respectively. Other common malformations were gallbladder agenesis, congenital diaphragmatic hernia, and neurocognitive abnormalities, mostly developmental delay. Fifty‐eight percent of the mutations were de novo, and these patients more often had an anomaly of intracardiac connections, an anomaly of the great arteries, and hypothyroidism, compared with those with inherited mutations. Functional studies mostly support loss‐of‐function as the pathophysiological mechanism. In conclusion, GATA6 mutations give a wide range of phenotypic defects, most frequently malformations of the heart and pancreas. This highlights the importance of detailed clinical evaluation of identified carriers to evaluate their full phenotypic spectrum.