Characterizing the morbid genome of ciliopathies.

Autor: Shaheen R; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Szymanska K; Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, LS9 7TF, UK., Basu B; Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, LS9 7TF, UK., Patel N; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Ewida N; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Faqeih E; Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia., Al Hashem A; Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia., Derar N; Department of Pediatrics, Division of Medical Genetics, Stanford University, Stanford, CA, USA., Alsharif H; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Aldahmesh MA; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Alazami AM; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Hashem M; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Ibrahim N; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Abdulwahab FM; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Sonbul R; Department of Pediatrics, Qatif Central Hospital, Qatif, Saudi Arabia., Alkuraya H; Department of Ophthalmology, Specialized Medical Center Hospital, Riyadh, Saudi Arabia., Alnemer M; Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Al Tala S; Department of Pediatric, Genetic Unit, Armed Forces Hospital Southern Region, Khamis Mushayt, Saudi Arabia., Al-Husain M; Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia., Morsy H; Human Genetics Department, Medical Research Institute, Alexandria University, Alexandria, Egypt., Seidahmed MZ; Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia., Meriki N; Department of Obstetrics and Gynecology, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia., Al-Owain M; 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., AlShahwan S; Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia., Tabarki B; Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia., Salih MA; Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia., Faquih T; Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia., El-Kalioby M; Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia., Ueffing M; Division of Experimental Ophthalmology and Medical Bioanalytics, Center for Ophthalmology, Eberhard-Karls University Tübingen, 72076, Tübingen, Germany., Boldt K; Division of Experimental Ophthalmology and Medical Bioanalytics, Center for Ophthalmology, Eberhard-Karls University Tübingen, 72076, Tübingen, Germany., Logan CV; Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, LS9 7TF, UK., Parry DA; Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, LS9 7TF, UK., Al Tassan N; 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., Monies D; 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., Megarbane A; Institut Jerome Lejeune, Paris, France., Abouelhoda M; 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., Halees A; Health Information Technology Affairs, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Johnson CA; Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, LS9 7TF, UK., Alkuraya FS; 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.
Jazyk: angličtina
Zdroj: Genome biology [Genome Biol] 2016 Nov 28; Vol. 17 (1), pp. 242. Date of Electronic Publication: 2016 Nov 28.
DOI: 10.1186/s13059-016-1099-5
Abstrakt: Background: 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.
Results: 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.
Conclusions: 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.
Databáze: MEDLINE
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