Haploinsufficiency of insulin gene enhancer protein 1 (ISL1) is associated with d‐transposition of the great arteries

Abstract

Congenital heart defects are the most common malformation, and are the foremost causes of mortality in the first year of life. Among congenital heart defects, conotruncal defects represent about 20% and are severe malformations with significant morbidity. Insulin gene enhancer protein 1 (ISL1) has been considered a candidate gene for conotruncal heart defects based on its embryonic expression pattern and heart defects induced in Isl1 knockout mice. Nevertheless no mutation of ISL1 has been reported from any human subject with a heart defect. From a population base of 974,579 births during 1999–2004, we used multiplex ligation-dependent probe amplification to screen for microdeletions/duplications of ISL1 among 389 infants with tetralogy of Fallot or d-transposition of the great arteries (d-TGA). We also sequenced all exons of ISL1. We identified a novel 20-kb microdeletion encompassing the entire coding region of ISL1, but not including either flanking gene, from an infant with d-TGA. We confirmed that the deletion was caused by nonhomologous end joining mechanism. Sequencing of exons of ISL1 did not reveal any subject with a novel nonsynonymous mutation. This is the first report of an ISL1 mutation of a child with a congenital heart defect.

Pioneering function of Isl1 in the epigenetic control of cardiomyocyte cell fate

“…S1a–d), 23 which survives until birth, allowing us to analyze the role of Isl1 in SHF structures that are dependent on Isl1, as well as during later stages of embryonic heart development. Consistent with human studies which identified ISL1 variations and deletions contributing to congenital heart disease, 16,17 all Isl1 hypomorphic mice ( Isl1 -f;neo/f;neo) died shortly after birth with severe cardiac malformations. Wholemount and histological analyses of Isl1 hypomorphic embryos at E12.5 (Fig.…”

“…Similarly, genetic variations in ISL1 have been associated with susceptibility to ventricular septal defect 43 and non-syndromic, complex congenital heart disease 17 in human patients, whereas ISL1 haploinsufficiency is associated with d-transposition of the great arteries. 16 Thus, our Isl1 hypomorphic mouse model represents a valuable genetic system to gain new insights into the etiology of congenital heart defects and for developing novel therapeutic strategies.…”

Disruption of spatiotemporal hypoxic signaling causes congenital heart disease in mice

“…Similarly to what occurs in Nkx2.5, mutations in the human Isl1 gene are associated with a diverse range of cardiac malformations (43)(44)(45). Therefore, it is not surprising that a complex netdistinction probably lies in the requirement of physiological hypoxia for embryonic heart development, while hypoxia is an unfavorable condition in most adult organs.…”

Data on single-step purification method for dye-labeled DNA sequencing

“…Dye-labeled DNA sequencing technique is still an important tool for clinical decision making on cancer [3] , [4] , [5] , drug metabolism genotyping [6] , [7] , [8] , pathogen identification [9] , [10] , [11] , inherited disease [12] , [13] , [14] , [15] , [16] , [17] and so on [18] , [19] . However, the methods remain laborious and time-consuming.…”