title: Characterizing the morbid genome of ciliopathies.
abstract: Ciliopathies are clinically diverse disorders of the primary cilium. Remarkable progress has been made in understanding the molecular basis of these genetically heterogeneous conditions; however, our knowledge of their morbid genome, pleiotropy, and variable expressivity remains incomplete.
  
  
  
  We applied genomic approaches on a large patient cohort of 371 affected individuals from 265 families, with phenotypes that span the entire ciliopathy spectrum. Likely causal mutations in previously described ciliopathy genes were identified in 85% (225/265) of the families, adding 32 novel alleles. Consistent with a fully penetrant model for these genes, we found no significant difference in their "mutation load" beyond the causal variants between our ciliopathy cohort and a control non-ciliopathy cohort. Genomic analysis of our cohort further identified mutations in a novel morbid gene TXNDC15, encoding a thiol isomerase, based on independent loss of function mutations in individuals with a consistent ciliopathy phenotype (Meckel-Gruber syndrome) and a functional effect of its deficiency on ciliary signaling. Our study also highlighted seven novel candidate genes (TRAPPC3, EXOC3L2, FAM98C, C17orf61, LRRCC1, NEK4, and CELSR2) some of which have established links to ciliogenesis. Finally, we show that the morbid genome of ciliopathies encompasses many founder mutations, the combined carrier frequency of which accounts for a high disease burden in the study population.
  
  
  
  Our study increases our understanding of the morbid genome of ciliopathies. We also provide the strongest evidence, to date, in support of the classical Mendelian inheritance of Bardet-Biedl syndrome and other ciliopathies.
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: Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, LS9 7TF, UK.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Szymanska
authors.affiliation: Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, LS9 7TF, UK.
authors.forename: Basudha
authors.initials: B
authors.lastname: Basu
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Nisha
authors.initials: N
authors.lastname: Patel
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Nour
authors.initials: N
authors.lastname: Ewida
authors.affiliation: Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
authors.forename: Eissa
authors.initials: E
authors.lastname: Faqeih
authors.affiliation: Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
authors.forename: Amal
authors.initials: A
authors.lastname: Al Hashem
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Stanford University, Stanford, CA, USA.
authors.forename: Nada
authors.initials: N
authors.lastname: Derar
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Hadeel
authors.initials: H
authors.lastname: Alsharif
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Aldahmesh
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Anas M
authors.initials: AM
authors.lastname: Alazami
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Mais
authors.initials: M
authors.lastname: Hashem
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.
authors.forename: Firdous M
authors.initials: FM
authors.lastname: Abdulwahab
authors.affiliation: Department of Pediatrics, Qatif Central Hospital, Qatif, Saudi Arabia.
authors.forename: Rawda
authors.initials: R
authors.lastname: Sonbul
authors.affiliation: Department of Ophthalmology, Specialized Medical Center Hospital, Riyadh, Saudi Arabia.
authors.forename: Hisham
authors.initials: H
authors.lastname: Alkuraya
authors.affiliation: Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Maha
authors.initials: M
authors.lastname: Alnemer
authors.affiliation: Department of Pediatric, Genetic Unit, Armed Forces Hospital Southern Region, Khamis Mushayt, Saudi Arabia.
authors.forename: Saeed
authors.initials: S
authors.lastname: Al Tala
authors.affiliation: Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Muneera
authors.initials: M
authors.lastname: Al-Husain
authors.affiliation: Human Genetics Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.
authors.forename: Heba
authors.initials: H
authors.lastname: Morsy
authors.affiliation: Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia.
authors.forename: Mohammed Zain
authors.initials: MZ
authors.lastname: Seidahmed
authors.affiliation: Department of Obstetrics and Gynecology, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Neama
authors.initials: N
authors.lastname: Meriki
authors.affiliation: Department of Medical 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: Mohammed
authors.initials: M
authors.lastname: Al-Owain
authors.affiliation: Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
authors.forename: Saad
authors.initials: S
authors.lastname: AlShahwan
authors.affiliation: Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
authors.forename: Brahim
authors.initials: B
authors.lastname: Tabarki
authors.affiliation: Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Mustafa A
authors.initials: MA
authors.lastname: Salih
authors.affiliation: Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
authors.forename: Tariq
authors.initials: T
authors.lastname: Faquih
authors.affiliation: Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Kalioby
authors.affiliation: Division of Experimental Ophthalmology and Medical Bioanalytics, Center for Ophthalmology, Eberhard-Karls University Tübingen, 72076, Tübingen, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Ueffing
authors.affiliation: Division of Experimental Ophthalmology and Medical Bioanalytics, Center for Ophthalmology, Eberhard-Karls University Tübingen, 72076, Tübingen, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Boldt
authors.affiliation: Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, LS9 7TF, UK.
authors.forename: Clare V
authors.initials: CV
authors.lastname: Logan
authors.affiliation: Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, LS9 7TF, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Parry
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
authors.forename: Nada
authors.initials: N
authors.lastname: Al Tassan
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
authors.forename: Dorota
authors.initials: D
authors.lastname: Monies
authors.affiliation: Institut Jerome Lejeune, Paris, France.
authors.forename: Andre
authors.initials: A
authors.lastname: Megarbane
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abouelhoda
authors.affiliation: Health Information Technology Affairs, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Anason
authors.initials: A
authors.lastname: Halees
authors.affiliation: Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, LS9 7TF, UK.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. medcaj@leeds.ac.uk.|Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia. medcaj@leeds.ac.uk.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. medcaj@leeds.ac.uk.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D000483:Alleles; D002923:Cilia / Q000235:genetics* / Q000473:pathology; D002925:Ciliary Motility Disorders / Q000235:genetics* / Q000473:pathology; D000072661:Ciliopathies / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D004677:Encephalocele / Q000235:genetics* / Q000473:pathology; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D007690:Polycystic Kidney Diseases / Q000235:genetics* / Q000473:pathology; D012160:Retina / Q000378:metabolism / Q000473:pathology; D012174:Retinitis Pigmentosa
keywords: Acrocallosal; Bardet-Biedl; Cilia; Founder; Joubert; Meckel-Gruber; Modifier; Nephronophthisis; Oligogenic; Oral-facial-digital; Polycystic kidney; Senior-Loken; Variability