Opportunities and Challenges for Molecular Understanding of Ciliopathies-The 100,000 Genomes Project

Abstract

Cilia are highly specialized cellular organelles that serve multiple functions in human development and health. Their central importance in the body is demonstrated by the occurrence of a diverse range of developmental disorders that arise from defects of cilia structure and function, caused by a range of different inherited mutations found in more than 150 different genes. Genetic analysis has rapidly advanced our understanding of the cell biological basis of ciliopathies over the past two decades, with more recent technological advances in genomics rapidly accelerating this progress. The 100,000 Genomes Project was launched in 2012 in the UK to improve diagnosis and future care for individuals affected by rare diseases like ciliopathies, through whole genome sequencing (WGS). In this review we discuss the potential promise and medical impact of WGS for ciliopathies and report on current progress of the 100,000 Genomes Project, reviewing the medical, technical and ethical challenges and opportunities that new, large scale initiatives such as this can offer.

Keywords: Genome Project; cilia; ciliopathies; genetics; genomics.

Figure 1

Proportion of families and individuals with different disorders within the rare disease cohort of the 100,000 Genomes Project. Around 1% of recruited families/individuals have a ciliopathy. Cohort summary data courtesy of Genomics England, with permission.

Figure 2

Overlapping disease features of the ciliopathies. This is not an exhaustive list but illustrates the complex phenotypes and overlapping clinical features of ciliopathies. The severe/lethal diseases tend to have more complex combinations of disease features, compared to diseases at the milder end of the clinical spectrum. Situs inversus and associated cardiac malformations are found in common between non-motile and motile ciliopathies and the former can also display respiratory defects. ALMS, Alström syndrome; BBS, Bardet-Biedl syndrome; JATD, Jeune asphyxiating thoracic dysplasia; JBTS, Joubert syndrome; LCA, Leber congenital amaurosis; MKS, Meckel-Gruber syndrome; NPHP, nephronophthisis; OFD, oral-facial-digital syndrome; PCD, primary ciliary dyskinesia; PKD, polycystic kidney disease; RP, retinitis pigmentosa; USH, Usher syndrome.

Figure 3

Schematic illustration of cytidine deaminase and adenine base editing of the genome. Abbreviations: sgRNA, single guide RNA; BE3, third generation base editor; ABE, adenine base editor.

Figure 4

Proportion of annotated human protein coding genes with specific functions. Data from pantherdb.org. Thirty-five percentage of human genes have an unknown function.