Publication highlights: May-July 2022
By Research Management team on
Below are some of the notable papers published in the last few months using data from the National Genomics Research Library. You can view the full range of publications being produced by our research community on our publications page.
Uncovering the burden of hidden ciliopathies in the 100,000 Genomes Project: a reverse phenotyping approach
Best et al., Journal of Medical Genetics 2022
Cilia were among the first described cellular organelles. They play critical roles in motile force generation and the reception and transduction of critical extracellular signals, but it is only in the last two decades that the extent of the influence of cilia on human health has become apparent.
Genetic variants that impair cilia structure and/or function are now known to underlie numerous congenital diseases, termed ciliopathies, which often share phenotypic features (e.g. craniofacial, laterality, cerebral, retinal, renal, skeletal and fertility abnormalities), but vary in their clinical presentation and severity. While whole genome sequencing and target gene panel analysis have improved molecular diagnosis for ciliopathy patients, the heterogeneity of cilia genetics and clinical phenotypes still hampers diagnosis for a significant fraction of patients.
In their paper, Best et al. describe a custom reverse phenotyping strategy to identify 100,000 Genomes Project participants with pathogenic variants in nine selected ciliopathy disease genes. Identified participants were then screened for the presence of at least one major clinical feature that was compatible with the implicated gene. In so doing, they identified 62 reportable molecular diagnoses with variants in these genes, including 5 previously unreported cases and 13 new diagnoses.
Their work demonstrates the power of reverse phenotyping strategies to increase molecular diagnosis rates and patient benefit in large scale genomic studies such as the 100,000 Genomes Project.
Genome sequencing reveals underdiagnosis of primary ciliary dyskinesia in bronchiectasis
Shoemark et al. European Respiratory Journal 2022
Bronchiectasis is lung disease characterised by permanent enlargement of the bronchial tubes and excess mucus levels. In the absence of a clinical diagnosis and proactive management, it can cause potentially life-threatening complications such as massive haemoptysis. While bronchiectasis can occur through infectious, genetic, immunological or allergic mechanisms, the precise cause is unknown in most clinical cases. Improved molecular diagnosis and understanding of aetiology would inform proactive management of likely complications and co-morbidities.
Primary ciliary dyskinesia (PCD), a motile ciliopathy, is one recognised genetic cause of bronchiectasis, and testing is recommended in patients with supporting clinical features. However, clinical PCD diagnosis is complex and there is a high risk of missed or late diagnosis.
In their recent paper, Shoemark and colleagues use genomic data from patients recruited to the 100,000 Genomes Project, gene panel data from patients referred for testing within a tertiary respiratory hospital, and PCD diagnostic data from the British Thoracic Society national audit to investigate whether motile ciliopathies are underdiagnosed in people with bronchiectasis. Analysis of 142 patient genomes identified pathogenetic variants in 17 individuals (12%), while gene panel testing produced a PCD diagnosis in 5 – 10% of cases. However, less that 1% of audited patients with bronchiectasis received genetic PCD testing.
Together, the data suggest that PCD is an underdiagnosed cause of bronchiectasis, and that increased genetic testing may reduce the number of unexplained cases and facilitate improved treatment.
The role of common genetic variation in presumed monogenic epilepsies
Campbell et al. EBioMedicine 2022
The developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies which co-present with developmental delay and intellectual disability (ID).
Using data from six cohorts of severe epilepsies, this study shows that DEEs and similar forms of epilepsy which present with intellectual disability have an increased burden of polygenic risk associated with complex forms of epilepsy. The researchers co-analyse polygenic burden with rare variant data and observe no difference in polygenic burden between cases with and without deleterious rare variants.
These results provide insight into the genetic underpinnings of the severe epilepsies and suggests our understanding of the aetiology of the DEEs should be as complex, rather than monogenic, disorders.
For more publications being produced by our research community, visit our publications page.
