Prof Angus Clarke
Dr Arveen Kamath
Cardiff and Vale University Health Board
Ectodermal dysplasia (ED) is not a single condition but a group of closely related genetic disorders affecting the development or function of the ectodermal structures – hair, teeth, nails, sweat glands, cranial-facial structure, parts of the eye and ear, digits, nerves and parts of some organs. Physical features vary greatly between affected individuals even for the same type of ED, and abnormalities range from mild to severe.
Cardiff is considered to be a centre of clinical excellence for the genetic aspects of ED. Currently, Laboratory Genetics provides a worldwide service for this disorder.
The current laboratory service is offered using an expensive, low-throughput sequencing technology that requires analysis of individual genes leading to high costs (£500-1,000 per gene).
The laboratory requires the validation of clinical exome sequencing to replace a single gene for the ED service; the required technology is Illumina’s TruSight One panel and HiSeq 2500 sequencing system. This will allow all clinically-relevant ED genes to be analysed at the same time, instead of individually as present.
Peripheral blood extracted DNA samples were collected from 32 patients with ED and 32 patient control samples. This cohort contained 69 unique variants identified using Sanger sequencing which were targeted for next-generation sequencing using the Illumina TruSight One clinical exome. Assay sensitivity was 100.00% (94.79% to 100.00% 95CI). The panel can detect single-nucleotide and small insertion-deletion (<~40bp) variants.
This Project Supports Prudent Healthcare
Positive patient outcomes increased:
Improve public health - increased diagnostic yield.
Improve patient care - deliver a genetic diagnosis that matters to families.
The opportunity to recognise interactions between genetic variants at functionally-related loci
Health system efficiency increased:
As a great exemplar of Prudent Healthcare, clinical exome analysis for patients with ED if undertaken early enough, could potentially:
Avoid needless clinical appointments in specialist clinics. Avoid additional investigations.
Patients often have to travel long distances to attend these clinics, sometimes out of Wales.
Prevent unnecessary investigations or treatments. By achieving a molecular diagnosis in a timely fashion, family-based testing can allow those at-risk but who are shown NOT to carry the family’s mutation to be removed from the additional recommended health monitoring and surveillance.
Avoid significant delays in patients receiving a diagnosis.
Provide timely genetic counselling for family members, in time for critical family planning decision-making.
It is cheaper than the current service due to the clinical uncertainty around the most likely gene responsible.
The precise gene and mutation involved will be therapeutically important in the future.
Impact of validating the clinical exome sequencing workflow for the laboratory:
Replace the current expensive Sanger sequencing for other rare genetic disease services.
Repatriation of rare genetic disease services currently sent to external laboratories.
Remain competitive in the field of genetic testing to deliver up to date patient services.
Improve the ability to attract and retain staff.
Part of Cohort Bevan Exemplars 2015-16