Molecular diagnoses in the congenital malformations caused by ciliopathies cohort of the 100,000 Genomes Project

Abstract

BackgroundPrimary ciliopathies represent a group of inherited disorders due to defects in the primary cilium, the ‘cell’s antenna’. The 100,000 Genomes Project was launched in 2012 by Genomics England (GEL), recruiting National Health Service (NHS) patients with eligible rare diseases and cancer. Sequence data were linked to Human Phenotype Ontology (HPO) terms entered by recruiting clinicians.MethodsEighty-three prescreened probands were recruited to the 100,000 Genomes Project suspected to have congenital malformations caused by ciliopathies in the following disease categories: Bardet-Biedl syndrome (n=45), Joubert syndrome (n=14) and ‘Rare Multisystem Ciliopathy Disorders’ (n=24). We implemented a bespoke variant filtering and analysis strategy to improve molecular diagnostic rates for these participants.ResultsWe determined a research molecular diagnosis for n=43/83 (51.8%) probands. This is 19.3% higher than previously reported by GEL (n=27/83 (32.5%)). A high proportion of diagnoses are due to variants in non-ciliopathy disease genes (n=19/43, 44.2%) which may reflect difficulties in clinical recognition of ciliopathies. n=11/83 probands (13.3%) had at least one causative variant outside the tiers 1 and 2 variant prioritisation categories (GEL’s automated triaging procedure), which would not be reviewed in standard 100,000 Genomes Project diagnostic strategies. These include four structural variants and three predicted to cause non-canonical splicing defects. Two unrelated participants have biallelic likely pathogenic variants in LRRC45, a putative novel ciliopathy disease gene.ConclusionThese data illustrate the power of linking large-scale genome sequence to phenotype information. They demonstrate the value of research collaborations in order to maximise interpretation of genomic data.

Unlocking the potential of the UK 100,000 Genomes Project—lessons learned from analysis of the “Congenital Malformations caused by Ciliopathies” cohort

“…In summary, the ciliopathies provide an exemplar group of disorders that illustrate both the challenges and opportunities of working with 100K datasets (Best et al, 2021; Wheway et al, 2019). 100K remains an immensely valuable clinical and scientific resource with huge potential for patient benefit, but that benefit has not yet been fully realized.…”

“…Tier 3 and un-tiered variants are not inspected routinely by NHS diagnostic labs, and left to external researchers to consider more fully, if at all. In our own work (Best et al, 2021), we identified 11/83 probands (13.3%) with research molecular diagnoses with at least one variant outside of tiers 1 and 2. Five tier 3 variants and 12 untiered variants contribute to the diagnoses for these 11 participants.…”

“…We reviewed sequencing, variant and clinical data from patients recruited to the “Congenital Malformations caused by Ciliopathies” (CMC) cohort of the UK 100,000 Genomes Project (100K) (Best et al, 2021). 1 By using domain‐specific knowledge of ciliopathy genetics (Reiter & Leroux, 2017; Wheway et al, 2019), and examining variants in non‐ciliopathy disease genes, we were able to identify potentially causative variants beyond those reported by the triaging process implemented by Genomics England (GEL, the company set up to run 100K).…”

The role of alternative splicing in CEP290-related disease pathogenesis

“…CEP290 has over 200 associated pathogenic variants spread throughout the full length of the gene. There are also 136 affected probands in the 100,000 Genomes Project datasets with biallelic likely pathogenic CEP290 variants and ciliopathy phenotypes (4, 5). However, there is no clear genotype-phenotype association between severe syndromic and isolated retinal disease-causing genotypes.…”

Interpreting ciliopathy-associated missense variants of uncertain significance (VUS) in Caenorhabditis elegans

“…Ciliopathies are a heterogenous group of at least 25 inherited disorders with clinically overlapping phenotypes, caused by pathogenic variants in >200 genes ( 13 , 14 ). Ciliopathies affect many organ systems, causing a broad range of clinical phenotypes of varied severity and penetrance that include cystic kidneys, retinal dystrophy, bone abnormalities, organ laterality defects, respiratory tract defects, infertility, obesity, neurodevelopmental defects and cognitive impairment ( 15 ).…”