当前位置： SCI文献检索 > JOURNAL OF MEDICAL GENETICS期刊下所有文献 > Positional mapping of PRKD1, NRP1 and PRDM1 as novel candidate disease genes in truncus arteriosus.

Positional mapping of PRKD1, NRP1 and PRDM1 as novel candidate disease genes in truncus arteriosus.

Abstract：

BACKGROUND:Truncus arteriosus (TA) is characterised by failure of septation of the outflow tract into aortic and pulmonary trunks and is associated with high morbidity and mortality. Although ranked among the least common congenital heart defects, TA provides an excellent model for the role of individual genes in cardiac morphogenesis as exemplified by TBX1 deficiency caused by point mutations or, more commonly, hemizygosity as part of the 22q11.2 deletion syndrome. The latter genetic lesion, however, is only observed in a proportion of patients with TA, which suggests the presence of additional disease genes. OBJECTIVE:To identify novel genes that cause Mendelian forms of TA. METHODS AND RESULTS:We exploited the occurrence of monogenic forms of TA in the Saudi population, which is characterised by high consanguinity, a feature conducive to the occurrence of Mendelian phenocopies of complex phenotypes as we and others have shown. Indeed, we demonstrate in two multiplex consanguineous families that we are able to map TA to regions of autozygosity in which whole-exome sequencing revealed homozygous truncating mutations in PRKD1 (encoding a kinase derepressor of MAF2) and NRP1 (encoding a coreceptor of vascular endothelial growth factor (VEGFA)). Previous work has demonstrated that Prkd1(-/-) is embryonic lethal and that its tissue-specific deletion results in abnormal heart remodelling, whereas Nrp1(-/-) develops TA. Surprisingly, molecular karyotyping to exclude 22q11.2 deletion syndrome in the replication cohort of 17 simplex TA cases revealed a de novo hemizygous deletion that encompasses PRDM1, deficiency of which also results in TA phenotype in mouse. CONCLUSIONS:Our results expand the repertoire of molecular lesions in chromatin remodelling and transcription factors that are implicated in the pathogenesis of congenital heart disease in humans and attest to the power of monogenic forms of congenital heart diseases as a complementary approach to dissect the genetics of these complex phenotypes.

journal_name

J Med Genet

journal_title

Journal of medical genetics

authors

Shaheen R,Al Hashem A,Alghamdi MH,Seidahmad MZ,Wakil SM,Dagriri K,Keavney B,Goodship J,Alyousif S,Al-Habshan FM,Alhussein K,Almoisheer A,Ibrahim N,Alkuraya FS

doi

10.1136/jmedgenet-2015-102992

subject

Has Abstract

pub_date

2015-05-01 00:00:00

pages

322-9

issue

eissn

0022-2593

issn

1468-6244

pii

jmedgenet-2015-102992

journal_volume

pub_type

杂志文章

在线工具

Positional mapping of PRKD1, NRP1 and PRDM1 as novel candidate disease genes in truncus arteriosus.