Genetic Testing

Genetic testing can be categorized by its purpose. Diagnostic testing is used to confirm or rule out a specific condition in a symptomatic individual. Predictive (presymptomatic) testing is used in healthy individuals with a family history of a late-onset condition, such as Huntington's or BRCA1/2. Carrier testing identifies individuals who carry one copy of a recessive gene. Prenatal testing (e.g., amniocentesis or non-invasive prenatal testing - NIPT) and pre-implantation genetic diagnosis (PGD) are used to assess the health of a fetus or embryo. Pharmacogenetic testing predicts response to specific drugs. Techniques vary: Karyotyping and FISH look at large chromosomal structures; microarrays detect small gains or losses of DNA (copy number variants); Sanger sequencing looks at single genes; and Next-Generation Sequencing (NGS) allows for gene panels or Whole Exome/Genome Sequencing. A critical aspect of modern testing is the interpretation of results: a 'Variant of Uncertain Significance' (VUS) means a change was found, but it is not yet known if it causes disease. This requires correlation with clinical findings and family studies. Consent is a cornerstone of the process, ensuring patients understand the implications for themselves and their relatives.

Molecular genetics relies on the principle of complementary base pairing. In PCR, specific primers bind to DNA, allowing targeted amplification. In microarrays (Array CGH), patient DNA and control DNA are labeled with different fluorescent dyes and hybridized to a chip containing thousands of DNA probes; if the patient has a deletion, that area of the chip will show the control color. Next-Generation Sequencing (NGS) involves fragmenting the whole genome, attaching adapters, and sequencing millions of pieces simultaneously ('in parallel'). Bioinformatics then 'aligns' these pieces back to a reference genome to find discrepancies. Understanding 'read depth' and 'coverage' is essential for NGS quality control. Epigenetic testing, such as looking for DNA methylation patterns (e.g., in Prader-Willi/Angelman syndromes), requires specialized techniques like bisulfite sequencing.

Genetic testing is revolutionizing medicine, allowing for 'precision medicine.' It is used in oncology to guide therapy (e.g., BRAF in melanoma), in rare disease diagnosis to end the 'diagnostic odyssey,' and in cardiology for inherited arrhythmias. In the UK, the NHS National Genomic Test Directory specifies which tests are available for which clinical indications. Clinicians must be aware of the ethical issues: the 'right not to know,' the implications for life insurance, and the potential for incidental findings (finding a mutation for a disease other than the one being tested for).

1. Chromosome analysis: Karyotype, FISH, Array CGH. 2. Molecular analysis: PCR, Sanger, NGS. 3. Biochemical genetics: Measuring levels of metabolites or enzymes that indirectly indicate a genetic defect. 4. Interpretation: Pathogenic, Likely Pathogenic, VUS, Likely Benign, or Benign.

Positive results lead to: 1. Targeted treatment. 2. Surveillance (e.g., frequent colonoscopies in Lynch syndrome). 3. Familial 'cascade testing' (offering testing to relatives). 4. Reproductive planning. Negative results in a symptomatic person may lead to WGS or further investigations if the index of suspicion remains high.