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Original article
Positional mapping of PRKD1, NRP1 and PRDM1 as novel candidate disease genes in truncus arteriosus
  1. Ranad Shaheen1,
  2. Amal Al Hashem2,3,
  3. Mohammed H Alghamdi4,
  4. Mohammed Zain Seidahmad5,
  5. Salma M Wakil1,
  6. Khalid Dagriri6,
  7. Bernard Keavney7,
  8. Judith Goodship8,
  9. Saad Alyousif5,
  10. Fahad M Al-Habshan9,
  11. Khalid Alhussein5,
  12. Agaadir Almoisheer1,
  13. Niema Ibrahim1,
  14. Fowzan S Alkuraya1,3
  1. 1Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  2. 2Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
  3. 3Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
  4. 4Department of Cardiac Sciences, College of Medicine, King Saud University, Riyadh, Saudi Arabia
  5. 5Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia
  6. 6Department of Pediatric Cardiology, Prince Sultan Cardiac Center, Riyadh, Saudi Arabia
  7. 7Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK
  8. 8Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
  9. 9Department of Cardiology, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
  1. Correspondence to Dr Fowzan S Alkuraya, Department of Genetics, King Faisal Specialist Hospital and Research Center, MBC-03 PO BOX 3354, Riyadh 11211, Saudi Arabia; falkuraya{at}


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.

  • Congenital heart disease
  • Mendelian form
  • cardiac morphogenesis
  • exome

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