Journal Article

Characterizing the morbid genome of ciliopathies

Al-Owain, Mohammed, Al Tassan, Nada, Monies, Dorota, Aldahmesh, Mohammed A., Ueffing, Marius, Shaheen, Ranad, Patel, Nisha, Alnemer, Maha, Al Tala, Saeed, Ewida, Nour, Meriki, Neama, Al Hashem, Amal, Abouelhoda, Mohamed, Tabarki, Brahim, AlShahwan, Saad, Abdulwahab, Firdous M., Basu, Basudha, Seidahmed, Mohammed Zain, Halees, Anason, Al-Husain, Muneera, Logan, Clare V., Megarbane, Andre, Sonbul, Rawda, Szymanska, Katarzyna, Johnson, Colin A., Parry, David A., Morsy, Heba, Boldt, Karsten, Salih, Mustafa A., Alkuraya, Fowzan S., Hashem, Mais, Derar, Nada, Alkuraya, Hisham, El-Kalioby, Mohamed, Faquih, Tariq, Alazami, Anas M., Alsharif, Hadeel, Faqeih, Eissa, Ibrahim, Niema

2016

Overview

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.

• Publisher: BioMed Central,Springer Nature B.V
• Subject: Alleles / Animal Genetics and Genomics / as Revealed Through Genomics / Bardet-Biedl syndrome / Bioinformatics / Biomedical and Life Sciences / burden of disease / Cell cycle / Cilia - genetics / Cilia - pathology / Ciliary Motility Disorders - genetics / Ciliary Motility Disorders - pathology / Ciliopathies - genetics / Ciliopathies - pathology / Congenital defects / Congenital diseases / Disease / DNA Mutational Analysis / Encephalocele - genetics / Encephalocele - pathology / Evolutionary Biology / Genes / Genetic Association Studies / Genetic Heterogeneity / Genetic Predisposition to Disease / Genomes / Genomic analysis / Genomics / Heredity / Human Genetics / Humans / Life Sciences / Mendelian inheritance / Microbial Genetics and Genomics / Mutation / Mutation - genetics / Neurodevelopmental disorders / patients / Phenotype / Phenotypes / Plant Genetics and Genomics / Pleiotropy / Polycystic Kidney Diseases - genetics / Polycystic Kidney Diseases - pathology / Population studies / Proteins / Retina - metabolism / Retina - pathology / Retinitis Pigmentosa / Studies / The Biology of Human Diseases / thiols