Rare and undiagnosed disease
For diagnostic pathways that have run for years without conclusion, the department returns to the genome and to the patient together. Sequencing is read alongside a detailed clinical account of the condition, since a variant means little without the phenotype it must explain, and data already generated elsewhere is reanalysed rather than repeated.
· Sequencing. Whole genome and whole exome sequencing, with long-read sequencing on the Institute’s own platform where structural variation is suspected.
· Phenotyping and interpretation. Detailed clinical characterisation, interpretation against current evidence, and reanalysis of sequencing undertaken elsewhere.
· What follows. Onward referral to the relevant specialist, with the finding explained and the pathway agreed before you leave.
Hereditary cancer risk
Inherited predisposition is identified so that the surveillance it warrants can begin, and so that relatives who share the risk can be offered testing. Counselling precedes every test and follows every result, because a finding here concerns a family rather than a person.
· Testing. BRCA1 and BRCA2, Lynch syndrome, and extended predisposition panels covering the genes with an established surveillance pathway.
· Counselling and planning. Counselling before and after testing by a clinical geneticist, and a surveillance plan agreed with the relevant specialist.
· Family. Cascade testing offered to relatives, arranged and counselled through the Institute.
Cardiac genetics
Inherited cardiac conditions are among the few causes of sudden death that can be found in advance, and among the most treatable once found. The department assesses inherited risk, including following a sudden or unexplained death in the family, and works with the relevant connecting department on what follows.
· Conditions. Inherited cardiomyopathies, inherited arrhythmia syndromes, familial hypercholesterolaemia and disorders of the aorta.
· Family screening. Cascade testing and clinical assessment of relatives where a variant is identified.
Reproductive and carrier screening
Reproductive risk can be established before conception rather than discovered during pregnancy, when the options are fewer. The department offers screening to individuals and couples, and investigation where conception has proved difficult.
· Screening. Expanded carrier screening across several hundred conditions, karyotype and chromosomal microarray.
· Investigation. Assessment in recurrent pregnancy loss and the genetics of male infertility.
· Counselling. Preconception counselling, with results interpreted for the couple together and the options set out in full.
Pharmacogenomics
Roughly one in five prescribed medicines is metabolised by a single enzyme, CYP2D6, whose gene is among the hardest in the genome to read correctly. The department resolves it, and the other principal metabolising enzymes, by long-read sequencing on the Institute’s own Oxford Nanopore platform, which reads the full structure of each gene where short-read methods and arrays cannot. This has applications for the use of antidepressants, anticoagulants, analgesics, statins and the wider range of medicines whose effect and tolerability depend on how they are metabolised. A written pharmacogenomic record held in your file and provided to any clinician treating you, so that nothing is prescribed without knowing how you will process it.
Precision oncology
Where cancer has been diagnosed, the biology of the tumour determines which treatments are likely to work. The department profiles it, identifies the variants for which targeted treatment exists, and follows the disease after treatment at a sensitivity conventional imaging cannot reach. This can include an assessment of clinical trial eligibility against the tumour’s profile.
Genomic risk assessment
Polygenic risk scores combine thousands of common variants into an estimate of predisposition to conditions such as coronary disease, diabetes and certain cancers. They are useful, and their limits are real: their accuracy varies by ancestry, and they estimate a tendency rather than a diagnosis. The department reports them with those limits stated and reads them alongside everything else that is known about you.
Reinterpretation
The genome does not change; what is known about it does. Your sequence is stored and returned to as the evidence advances, so that a variant of uncertain significance today can be resolved tomorrow without sequencing you again.
