Characterizing the morbid genome of ciliopathies

Genome Biol. 2016 Nov 28;17(1):242. doi: 10.1186/s13059-016-1099-5.

Ranad Shaheen ¹, Katarzyna Szymanska ², Basudha Basu ², Nisha Patel ¹, Nour Ewida ¹, Eissa Faqeih ³, Amal Al Hashem ⁴, Nada Derar ⁵, Hadeel Alsharif ¹, Mohammed A Aldahmesh ¹, Anas M Alazami ¹, Mais Hashem ¹, Niema Ibrahim ¹, Firdous M Abdulwahab ¹, Rawda Sonbul ⁶, Hisham Alkuraya ⁷, Maha Alnemer ⁸, Saeed Al Tala ⁹, Muneera Al-Husain ¹⁰, Heba Morsy ¹¹, Mohammed Zain Seidahmed ¹², Neama Meriki ¹³, Mohammed Al-Owain ¹⁴ ¹⁵, Saad AlShahwan ⁴, Brahim Tabarki ⁴, Mustafa A Salih ¹⁰, Ciliopathy WorkingGroup, Tariq Faquih ¹⁶, Mohamed El-Kalioby ¹⁶, Marius Ueffing ¹⁷, Karsten Boldt ¹⁷, Clare V Logan ², David A Parry ², Nada Al Tassan ¹ ¹⁶, Dorota Monies ¹ ¹⁶, Andre Megarbane ¹⁸, Mohamed Abouelhoda ¹ ¹⁶, Anason Halees ¹⁹, Colin A Johnson ², Fowzan S Alkuraya ²⁰ ²¹ ²²

Affiliations

1 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
2 Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, LS9 7TF, UK.
3 Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
4 Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
5 Department of Pediatrics, Division of Medical Genetics, Stanford University, Stanford, CA, USA.
6 Department of Pediatrics, Qatif Central Hospital, Qatif, Saudi Arabia.
7 Department of Ophthalmology, Specialized Medical Center Hospital, Riyadh, Saudi Arabia.
8 Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
9 Department of Pediatric, Genetic Unit, Armed Forces Hospital Southern Region, Khamis Mushayt, Saudi Arabia.
10 Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia.
11 Human Genetics Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.
12 Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia.
13 Department of Obstetrics and Gynecology, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia.
14 Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
15 Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
16 Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
17 Division of Experimental Ophthalmology and Medical Bioanalytics, Center for Ophthalmology, Eberhard-Karls University Tübingen, 72076, Tübingen, Germany.
18 Institut Jerome Lejeune, Paris, France.
19 Health Information Technology Affairs, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
20 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. medcaj@leeds.ac.uk.
21 Saudi Human Genome Project, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia. medcaj@leeds.ac.uk.
22 Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. medcaj@leeds.ac.uk.

PMID: 27894351 DOI: 10.1186/s13059-016-1099-5

Abstract

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.

Keywords

Acrocallosal; Bardet-Biedl; Cilia; Founder; Joubert; Meckel-Gruber; Modifier; Nephronophthisis; Oligogenic; Oral-facial-digital; Polycystic kidney; Senior-Loken; Variability.

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