title: Genetic profiling of children with advanced cholestatic liver disease.
abstract: Advanced cholestatic liver disease is a leading referral to pediatric liver transplant centers. Recent advances in the genetic classification of this group of disorders promise a highly personalized management although the genetic heterogeneity also poses a diagnostic challenge. Using a next-generation sequencing-based multi-gene panel, we performed retrospective analysis of 98 pediatric patients who presented with advanced cholestatic liver disease. A likely causal mutation was identified in the majority (61%), spanning many genes including ones that have only rarely been reported to cause cholestatic liver disease, e.g. TJP2 and VIPAS39. We find no evidence to support mono-allelic phenotypic expression in the carrier parents despite the severe nature of the respective mutations, and no evidence of oligogenicity. The high-carrier frequency of the founder mutations identified in our cohort (1 in 87) suggests a minimum incidence of 1:7246, an alarmingly high disease burden that calls for the primary prevention through carrier screening.
authors.affiliation: Organ Transplant Centre, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Department of Medicine, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: M
authors.initials: M
authors.lastname: Shagrani
authors.affiliation: Organ Transplant Centre, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: J
authors.initials: J
authors.lastname: Burkholder
authors.affiliation: Organ Transplant Centre, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: D
authors.initials: D
authors.lastname: Broering
authors.affiliation: Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.|Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: M
authors.initials: M
authors.lastname: Abouelhoda
authors.affiliation: Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.|Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: T
authors.initials: T
authors.lastname: Faquih
authors.affiliation: Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.|Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: M
authors.initials: M
authors.lastname: El-Kalioby
authors.affiliation: Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.|Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: S N
authors.initials: SN
authors.lastname: Subhani
authors.affiliation: Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.|Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: E
authors.initials: E
authors.lastname: Goljan
authors.affiliation: Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
authors.forename: R
authors.initials: R
authors.lastname: Albar
authors.affiliation: Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.|Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: D
authors.initials: D
authors.lastname: Monies
authors.affiliation: Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
authors.forename: N
authors.initials: N
authors.lastname: Mazhar
authors.affiliation: Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
authors.forename: B S
authors.initials: BS
authors.lastname: AlAbdulaziz
authors.affiliation: Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
authors.forename: K A
authors.initials: KA
authors.lastname: Abdelrahman
authors.affiliation: Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.|Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: N
authors.initials: N
authors.lastname: Altassan
authors.affiliation: Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.|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: F S
authors.identifier: http://orcid.org/0000-0003-4158-341X
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002779:Cholestasis / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008107:Liver Diseases / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D033921:Vesicular Transport Proteins / Q000235:genetics*; D055815:Young Adult; D062827:Zonula Occludens-2 Protein / Q000235:genetics*
chemical_list: C569046:TJP2 protein, human; C539711:VIPAS39 protein, human; D033921:Vesicular Transport Proteins; D062827:Zonula Occludens-2 Protein
keywords: cholestasis; personalized medicine; tight-junction; transplant