Molecular diagnoses in the congenital malformations caused by ciliopathies cohort of the 100,000 Genomes Project
Background A group of inherited disorders that are attributed to defects in the primary cilium or the ‘cell’s antenna’ are called primary ciliopathies. In 2012, Genomics England or GE spearheaded the 100,000 Genomes Project and recruited National Health Service or NHS patients with eligible rare diseases and cancer. The sequence data from this project were associated with Human Phenotype Ontology or HPO terms entered by recruiting clinicians. With that, the objective of this study is to optimize strategies to improve molecular diagnostic rates for probands recruited to the CMC category within the 100,000 Genomes Project. Method The researchers recruited 83 prescreened probands, which are assumed to have congenital anomalies and malformations caused by ciliopathies in the following disease categories: Bardet-Biedl syndrome, Joubert syndrome, and ‘Rare Multisystem Ciliopathy Disorders.’ The researchers implemented bespoke variant filtering and analysis strategy in order to enhance molecular diagnostic rates for participants. In addition, first-pass analysis was blinded to previous results, and then verified against the GEL reported findings in the GMC exit questionnaires. These were completed by regional NHS GMCs for each analysed participant. According to researchers, study analysis workflow comprised steps to filter genomic data, assess putative pathogenic variants then classify and assign diagnostic confidence. Key Findings The researchers established a research molecular diagnosis for half of probands and it appeared to be 20% higher than previously reported by GEL. According to researchers, a high proportion of diagnoses are correlated to variants in non-ciliopathy disease genes. These can hamper the clinical recognition of ciliopathies. Additionally, 13% of probands acquired at least one causative variant outside the tiers 1 and 2 variant prioritisation categories, however these are not included in standard 100,000 Genomes Project diagnostic strategies. These include four structural variants and three predicted to cause non-canon-ical splicing defects. The researchers also stated that two unrelated participants have biallelic likely pathogenic variants in LRRC45, a putative novel ciliopathy disease gene Conclusions and Recommendations The researchers therefore concluded that large-scale genomic sequencing and phenotyping, such as the 100,000 Genomes Project, have immense influence over the data that could offer huge opportunities to improve diagnostics, understanding of disease mechanisms and identification of novel drug targets. The researchers highlighted the need to improve strategies to analyse sequence data to provide the maximum benefit for patients and the scientific community.
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