title: 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.
  
  
  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.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Ranad
authors.initials: R
authors.lastname: Shaheen
authors.affiliation: Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: Amal
authors.initials: A
authors.lastname: Al Hashem
authors.affiliation: Department of Cardiac Sciences, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Mohammed H
authors.initials: MH
authors.lastname: Alghamdi
authors.affiliation: Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia.
authors.forename: Mohammed Zain
authors.initials: MZ
authors.lastname: Seidahmad
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Salma M
authors.initials: SM
authors.lastname: Wakil
authors.affiliation: Department of Pediatric Cardiology, Prince Sultan Cardiac Center, Riyadh, Saudi Arabia.
authors.forename: Khalid
authors.initials: K
authors.lastname: Dagriri
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK.
authors.forename: Bernard
authors.initials: B
authors.lastname: Keavney
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Judith
authors.initials: J
authors.lastname: Goodship
authors.affiliation: Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia.
authors.forename: Saad
authors.initials: S
authors.lastname: Alyousif
authors.affiliation: Department of Cardiology, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
authors.forename: Fahad M
authors.initials: FM
authors.lastname: Al-Habshan
authors.affiliation: Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia.
authors.forename: Khalid
authors.initials: K
authors.lastname: Alhussein
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Agaadir
authors.initials: A
authors.lastname: Almoisheer
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Niema
authors.initials: N
authors.lastname: Ibrahim
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D002648:Child; D002874:Chromosome Mapping; D003241:Consanguinity; D004452:Echocardiography; D059472:Exome; D017809:Fatal Outcome; D005260:Female; D005808:Genes, Recessive; D056726:Genetic Association Studies; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D039942:Neuropilin-1 / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011493:Protein Kinase C / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D014339:Truncus Arteriosus, Persistent / Q000175:diagnosis / Q000235:genetics*
chemical_list: D012097:Repressor Proteins; C087042:PRDM1 protein, human; D039942:Neuropilin-1; D000074462:Positive Regulatory Domain I-Binding Factor 1; C089212:protein kinase D; D011493:Protein Kinase C
keywords: Congenital heart disease; Mendelian form; cardiac morphogenesis; exome