The genetic alterations leading to congenital heart defects (CHD) are still poorly understood. We and others have recently shown that in mice loss of Hey2 results in a high incidence of fatal ventricular and atrial septal defects, combined with tricuspid stenosis or atresia in some cases. The phenotype has been postulated to resemble human tetralogy of Fallot. Our analysis of CD1 outbred mice suggests that phenotypic consequences of Hey2 loss can be quite variable and dependent on modifier genes as we detected only isolated VSDs with lower prevalence and a significantly reduced mortality rate in this strain. Since Hey2 is one of the few Notch target genes, it is also conceivable that HEY2 mutations may account for cases of Alagille syndrome (AGS: variable combinations of heart, skeleton, eye, and facial malformations and cholestasis), in which the typical mutations of the Notch ligand JAG1 cannot be found. To clarify the role of HEY2 in human CHD and AGS, we screened by direct sequencing 23 children with CHD and 38 patients diagnosed with AGS, which lack mutations in the JAG1 gene. We found two types of silent changes in the coding region: a CTT→CTG transition in exon 3 and a CTG→CTC polymorphism in exon 5. Furthermore, a heterozygous SNP in the splice donor site of exon 4 was detected that is unlikely to disrupt splicing. Although the high incidence and variability of human congenital heart defects implies a multifactorial genetic basis, our results suggest that mutation of HEY2 is not a major contributing factor.
Mammalian Genome – Springer Journals
Published: Jan 1, 2004
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