Clinical Genetics: Genetic testing, genomic medicine and counselling

• The NHS service: The NHS Genomic Medicine Service | When to Consider a Genetic Test or Referral | Mainstreaming -Genetic Testing Outside Clinical Genetics
• The tests: Karyotype, FISH and QF-PCR | Chromosomal Microarray | Sequencing -Single Gene, Panels, Exome and Genome | Targeted Tests -Repeat Expansions, MLPA and Methylation | Choosing the Right Test | Somatic (Tumour) Testing and Liquid Biopsy
• Results: Variant Classification and VUS | Interpreting and Communicating Results | Incidental and Secondary Findings
• People: Genetic Counselling | Diagnostic, Predictive and Carrier Testing | Cascade Testing and Informing Relatives
• Revision: Genetic Tests at a Glance | Spot the Diagnosis | Exam-style Scenarios | Key Points | Guidelines and Further Reading

🧬 Genetic testing, genomic medicine and counselling -page 2 of the Clinical Genetics chapter. Since 2018 England has had a single NHS Genomic Medicine Service, with a national directory of which tests can be ordered, for whom and by whom. Whole genome sequencing is now part of routine care for some rare diseases and cancers. Doctors in every specialty need to know what each test can and can't detect, how to consent for it, and how to explain a result -including an uncertain one.
Your four questions for every genetic test: What question am I asking -and which test answers it? Is the test in the National Genomic Test Directory for this patient? Has the patient consented, understanding the implications for relatives? How will I act on a positive, negative or uncertain result?

The NHS Genomic Medicine Service

• NHS Genomic Medicine Service (GMS) -launched in England in 2018 after the 100,000 Genomes Project (2012–2018, rare disease and cancer whole genome sequencing).
• Genomic Laboratory Hubs -a national network of 7 regional laboratory hubs carrying out NHS genomic testing.
• NHS Genomic Medicine Service Alliances -regional networks that help embed genomics into mainstream care.
• National Genomic Test Directory -lists every commissioned genomic test (rare and inherited disease, and cancer), the clinical indications, eligibility criteria and which specialties can request it.
• Whole genome sequencing -available on the NHS for selected indications (e.g. rare disease in children, acutely unwell children in intensive care, some cancers -paediatric cancers, sarcomas, haematological cancers).
• Genomics England -runs research programmes including the Generation Study (whole genome sequencing of newborns to look for treatable rare conditions).
• Devolved nations -Scotland, Wales and Northern Ireland have their own genetic services and test arrangements.
• Clinical genetics services -regional centres with clinical geneticists and genetic counsellors for diagnosis, counselling, predictive testing and family management.

When to Consider a Genetic Test or Referral

• Children -developmental delay or learning disability (especially with dysmorphism, epilepsy, autism or congenital anomalies), two or more congenital anomalies, unusual growth, suspected syndrome, unexplained hypotonia, neuromuscular disease, inborn error of metabolism.
• Family history -a known genetic condition in the family; a pattern suggesting inherited cancer, cardiomyopathy, arrhythmia or familial hypercholesterolaemia; sudden cardiac death under 40.
• Adults -early-onset or unusual disease (e.g. early-onset dementia, young stroke, early-onset cancer, multiple primary tumours), progressive neurological disease (ataxia, neuropathy, muscular dystrophy), inherited kidney disease, hearing or sight loss in young people.
• Reproductive -recurrent miscarriage (parental karyotype after a miscarriage with an unbalanced chromosomal rearrangement), stillbirth or fetal anomaly, infertility (Klinefelter syndrome, Y chromosome microdeletion, CFTR in congenital absence of the vas deferens), consanguineous couples planning a family, known carriers.
• Treatment decisions -cancer (somatic and germline variants guiding therapy, e.g. PARP inhibitors in BRCA), pharmacogenomics (e.g. DPYD before fluoropyrimidines -see page 6), CFTR modulators in cystic fibrosis.
• Refer to clinical genetics for predictive testing, complex family histories, uncertain results, reproductive options, syndrome diagnosis and family counselling.

Mainstreaming -Genetic Testing Outside Clinical Genetics

• Mainstreaming -genetic testing ordered by the treating team (oncology, cardiology, neurology, renal, paediatrics, obstetrics) rather than clinical genetics, using Test Directory criteria.
• Examples:
  • Oncology -germline BRCA testing in ovarian cancer and selected breast, prostate and pancreatic cancers; Lynch syndrome testing after a mismatch repair-deficient tumour.
  • Cardiology -cardiomyopathy and arrhythmia gene panels in inherited cardiac conditions clinics.
  • Lipid clinics -familial hypercholesterolaemia panel.
  • Neurology -neuromuscular, epilepsy and ataxia panels.
  • Haematology -haemoglobinopathies, bleeding disorders.
• The ordering clinician must -confirm eligibility, take informed consent, discuss implications for relatives, interpret and communicate the result, and refer to clinical genetics for positive or uncertain results needing family follow-up.
• Record-keeping -document consent (national record of discussion forms), results and advice given to relatives.

Karyotype, FISH and QF-PCR

• Karyotype -chromosomes stained and viewed under a microscope (G-banding):
  • Detects aneuploidy (trisomies, Turner, Klinefelter) and large structural changes -balanced translocations, inversions, large deletions (about 5–10 megabases or more).
  • Key use -balanced rearrangements (which microarray can't detect) -e.g. parents after recurrent miscarriage or a child with an unbalanced translocation; confirming the type of Down syndrome (Robertsonian translocation).
  • Needs dividing cells (blood lymphocytes, amniocytes, chorionic villi); results take days to weeks.
• FISH (fluorescence in situ hybridisation) -fluorescent probes for a specific region -detects targeted deletions or duplications (e.g. 22q11.2, Williams syndrome), rapid aneuploidy screens, and gene fusions in cancer (e.g. HER2 amplification, BCR–ABL1). Largely replaced by microarray for constitutional testing.
• QF-PCR (quantitative fluorescent PCR) -rapid aneuploidy testing for chromosomes 13, 18, 21, X and Y -results in 1–3 days on prenatal samples (CVS, amniocentesis) or urgent newborn samples.

Chromosomal Microarray

• Chromosomal microarray (array CGH or SNP array) -compares patient DNA with reference DNA across the genome to detect copy number variants (deletions and duplications) far smaller than a karyotype can see.
• First-line test for:
  • Developmental delay, learning disability and autism with additional features.
  • Multiple congenital anomalies.
  • Fetal structural anomalies on ultrasound (after QF-PCR).
• Detects -microdeletion syndromes (22q11.2 deletion, Williams, Smith–Magenis, 1p36 deletion), unbalanced translocations, aneuploidy; SNP arrays also detect uniparental disomy and regions of homozygosity (suggesting consanguinity).
• Doesn't detect -balanced translocations or inversions, single-gene sequence variants, small insertions or deletions, repeat expansions (fragile X), low-level mosaicism, methylation (imprinting) defects.
• Results -may find variants of uncertain significance; testing the parents often helps (an inherited CNV in a healthy parent is often benign, though reduced penetrance occurs -e.g. 15q11.2 and 16p11.2 susceptibility loci).
• Increasingly replaced by whole genome sequencing, which can detect CNVs and sequence variants together.

Sequencing -Single Gene, Panels, Exome and Genome

• Sanger sequencing -reads one gene region accurately -used for a known family variant (cascade testing, prenatal tests) and confirming NGS findings.
• Next-generation sequencing (NGS) -sequences millions of DNA fragments at once:
  • Gene panels -a set of genes for a clinical presentation (e.g. cardiomyopathy, hereditary breast and ovarian cancer, epilepsy) -focused, fewer uncertain findings.
  • Whole exome sequencing -the protein-coding regions of all genes (about 1–2% of the genome) -usually analysed with a "virtual panel" relevant to the phenotype.
  • Whole genome sequencing -the entire genome including non-coding regions -detects sequence variants, CNVs and some structural variants and repeat expansions in one test; best done as a trio (child and both parents) to find de novo variants.
• Diagnostic yield -whole genome sequencing gives a diagnosis in about a quarter to a third of children with suspected rare disease; many remain undiagnosed (data can be reanalysed later).
• Rapid whole genome sequencing -results within days for critically ill babies and children in NICU or PICU -can change management quickly.
• Limitations of NGS -may miss repeat expansions, some structural variants, mosaicism at low level, regions with homologous genes (pseudogenes); results depend on the phenotype information provided (the better the clinical details, the better the analysis -use HPO terms).

Targeted Tests -Repeat Expansions, MLPA and Methylation

• Repeat expansion testing (PCR with repeat-primed PCR or Southern blot) -Huntington's disease (HTT CAG), myotonic dystrophy (DMPK CTG), fragile X (FMR1 CGG), Friedreich's ataxia (FXN GAA), spinocerebellar ataxias, C9orf72 (motor neurone disease and frontotemporal dementia).
• MLPA (multiplex ligation-dependent probe amplification) -detects deletions or duplications of exons -e.g. Duchenne muscular dystrophy (most are exon deletions), spinal muscular atrophy (SMN1 exon 7 deletion), BRCA1 large rearrangements.
• Methylation testing -imprinting disorders -Prader–Willi and Angelman (15q11–q13), Beckwith–Wiedemann, Silver–Russell.
• Targeted variant testing -common variants -HFE C282Y and H63D (haemochromatosis), factor V Leiden, prothrombin G20210A, HbS (and haemoglobin electrophoresis or HPLC -a protein test, not DNA).
• Biochemical tests still matter -enzyme assays (lysosomal storage disease), amino acids, acylcarnitines, CK (muscle disease), sweat chloride (CF), ferritin and transferrin saturation (haemochromatosis).

Choosing the Right Test

Somatic (Tumour) Testing and Liquid Biopsy

• Somatic testing -sequencing tumour DNA to guide treatment:
  • Lung cancer -EGFR, ALK, ROS1, KRAS G12C, BRAF, MET, RET, NTRK, PD-L1 (immunohistochemistry).
  • Colorectal cancer -RAS and BRAF (anti-EGFR therapy), mismatch repair or MSI status (immunotherapy and Lynch screening).
  • Breast cancer -HER2, oestrogen receptor, PIK3CA; gene expression profiling (e.g. Oncotype DX) for chemotherapy decisions.
  • Melanoma -BRAF V600.
  • Haematological cancers -BCR–ABL1 (CML), JAK2 V617F (myeloproliferative neoplasms), FLT3 and NPM1 (AML), TP53 (CLL).
  • Ovarian cancer -BRCA1/2 and homologous recombination deficiency (PARP inhibitors).
• Germline implications -a tumour test can reveal a variant that might be inherited (e.g. BRCA in tumour) -confirm with a blood (germline) test and counsel about relatives.
• Liquid biopsy -circulating tumour DNA (ctDNA) in blood -detects targetable variants when tissue is limited (e.g. EGFR in lung cancer), monitors resistance and minimal residual disease; NHS England has rolled out ctDNA testing for lung cancer and some other cancers.
• Non-invasive prenatal testing also uses cell-free DNA (placental -see page 6).

Variant Classification and VUS

• Five-tier classification (ACMG/AMP, adapted for the UK by ACGS):
  1. Pathogenic (class 5) -disease-causing -can be used for diagnosis, predictive testing and reproductive decisions.
  2. Likely pathogenic (class 4) -over 90% probability -usually managed as pathogenic.
  3. Variant of uncertain significance (VUS) (class 3) -not enough evidence either way.
  4. Likely benign (class 2).
  5. Benign (class 1).
• Evidence used -population frequency (common variants are usually benign -gnomAD), type of variant (nonsense or frameshift in a loss-of-function gene), segregation with disease in the family, de novo status, functional studies, computer predictions, previous reports (ClinVar).
• A VUS must not be used for clinical decisions -don't test relatives for it predictively, don't offer risk-reducing surgery or prenatal diagnosis based on it; manage according to family history and clinical findings.
• Reclassification -VUSs are often reclassified (most become benign) as evidence accumulates; laboratories may issue updated reports -ensure a system for recontacting.
• VUS rates are higher in people of non-European ancestry (less reference data) -a recognised equity issue.

⚠️ Safety Pearl: A VUS is not a positive result. Never offer predictive testing, prenatal diagnosis or risk-reducing surgery on the basis of a VUS -manage on the clinical picture and family history, and refer to clinical genetics.

Interpreting and Communicating Results

• Positive (pathogenic) result -confirms the diagnosis; guides management, surveillance and treatment; enables predictive and cascade testing of relatives and reproductive options.
• Negative result -interpret in context:
  • "True negative" -the known family variant has been tested and is absent -the person's risk falls to population level (for that condition).
  • "Uninformative negative" -no variant found in an affected person or when no family variant is known -doesn't exclude a genetic cause (the variant may be in another gene or undetectable by the test); manage according to the family history (e.g. continue enhanced breast screening).
• Uncertain result -explain clearly, avoid over-interpretation, arrange follow-up and potential reclassification.
• Communicating -face-to-face or by planned telephone call; plain language; written summary letter; check understanding; discuss implications for relatives (give a family letter); offer psychological support and patient organisations (e.g. Genetic Alliance UK, Unique for chromosomal disorders).
• Results belong to the patient -but have implications for relatives (shared information -see page 6).

Incidental and Secondary Findings

• Incidental findings -unexpected results unrelated to the reason for testing (e.g. a BRCA1 variant found during genome sequencing for a child's learning disability; non-paternity or consanguinity revealed by trio testing; a sex chromosome anomaly on fetal microarray).
• Secondary findings -deliberately looked for in a list of "actionable" genes (the US ACMG list); in the NHS, analysis is usually restricted to genes relevant to the clinical question to minimise incidental findings.
• Consent should cover -the possibility of incidental findings, which findings would be reported (usually only those that are clinically significant and actionable), and the patient's wishes.
• Misattributed parentage -discovered through trio testing; handled sensitively with clinical genetics; usually not disclosed unless clinically relevant to the result.
• Direct-to-consumer tests (e.g. ancestry and health kits) -limited and sometimes inaccurate; don't replace clinical testing; results need confirmation in an accredited NHS laboratory before clinical action.

Genetic Counselling

• Genetic counselling -a communication process helping people understand and adapt to the medical, psychological and family implications of genetic conditions.
• Delivered by -clinical geneticists and genetic counsellors (registered healthcare professionals), and increasingly mainstream clinicians.
• Components:
  • Taking a detailed family history and confirming diagnoses.
  • Risk assessment and explaining inheritance.
  • Discussing testing options, benefits, limitations and implications.
  • Supporting decision-making -non-directive (helping people reach their own decision, especially on reproductive choices).
  • Psychological support -guilt, anxiety, grief, "survivor guilt" in those who test negative.
  • Reproductive options -natural conception with or without prenatal diagnosis, preimplantation genetic testing (PGT-M) with IVF, donor gametes, adoption, choosing not to have children.
• Interpreter and cultural considerations -use professional interpreters (not family members); consider beliefs about consanguinity, disability and termination.

Diagnostic, Predictive and Carrier Testing

• Diagnostic testing -to confirm or exclude a diagnosis in someone with symptoms.
• Predictive (presymptomatic) testing -in a healthy person at risk of a later-onset condition with a known family variant:
  • Huntington's disease, familial cancer syndromes, inherited cardiac conditions, familial hypercholesterolaemia.
  • Protocol (especially for untreatable conditions like Huntington's) -at least two pre-test counselling sessions, a reflection period, discussion of insurance, employment and psychological impact, a plan for receiving results and follow-up support.
  • "Presymptomatic" vs "predisposition" -a positive Huntington's test predicts disease almost certainly; a positive BRCA test indicates increased risk, not certainty.
• Carrier testing -for recessive or X-linked conditions in relatives or partners (e.g. CF, haemoglobinopathies, DMD, haemophilia).
• Testing children (BSGM and RCPCH guidance):
  • Test when results change management in childhood (e.g. familial adenomatous polyposis, MEN2, familial hypercholesterolaemia, inherited cardiac conditions).
  • Defer predictive testing for adult-onset conditions with no childhood intervention (e.g. Huntington's, BRCA) until the child can decide for themselves.
  • Carrier testing in children is usually deferred until they can understand it.
• Prenatal testing -CVS, amniocentesis, NIPT (see page 6).

Cascade Testing and Informing Relatives

• Cascade testing -once a pathogenic variant is identified in a family, at-risk relatives are offered targeted testing, one degree of relationship at a time.
• Benefits -finds at-risk people before disease develops; allows surveillance or prevention (e.g. statins in FH, colonoscopy in Lynch syndrome, ICDs in inherited arrhythmias); reassures those who test negative (who can stop surveillance).
• Familial hypercholesterolaemia -NICE recommends systematic cascade testing of first-, second- and (where possible) third-degree relatives.
• How relatives are informed -usually by the patient (supported by a family letter from the clinical team explaining the condition, the risk and how to get tested); clinical genetics services can help coordinate across regions.
• Confidentiality -the patient's consent is usually needed to share information; in rare cases, disclosure without consent may be justified to prevent serious harm (ABC v St George's Healthcare NHS Trust, 2020 -see page 6).
• Uptake -often incomplete (family estrangement, poor understanding) -follow-up and support improve it.

Genetic Tests at a Glance

Spot the Diagnosis

Exam-style Scenarios

1. A 3-year-old has global developmental delay, a heart murmur and subtle dysmorphic features. Parents are well. What genetic test should be done first?
Answer: Chromosomal microarray or whole genome sequencing (according to the Test Directory), ideally as a trio.

• Microarray detects microdeletions such as 22q11.2 or Williams syndrome; genome sequencing detects single-gene and copy number variants.
• Consider fragile X testing; echocardiogram; developmental assessment.
• Refer to clinical genetics; consent should cover incidental findings and implications for relatives.

2. A 42-year-old woman with breast cancer has a BRCA1 "variant of uncertain significance". Her sister asks to be tested for it.
Answer: Don't offer predictive testing for a VUS.

• A VUS isn't clinically actionable -her sister's risk is assessed from the family history (and she may be eligible for enhanced screening on that basis).
• The laboratory may reclassify the variant; segregation testing in other affected relatives may help -under clinical genetics.
• Explain clearly and arrange recontact if reclassified.

3. A woman has had three first-trimester miscarriages. Pregnancy tissue from the last one showed an unbalanced translocation.
Answer: Possible parental balanced translocation.

• Offer karyotyping of both parents (microarray won't detect balanced rearrangements).
• If a carrier -genetic counselling about recurrence risk, prenatal diagnosis and preimplantation genetic testing.
• Other recurrent miscarriage investigations -antiphospholipid antibodies, pelvic ultrasound (RCOG).

4. A cardiologist finds a pathogenic MYBPC3 variant in a 35-year-old man with hypertrophic cardiomyopathy. He has two children aged 10 and 14.
Answer: Cascade testing for first-degree relatives.

• Offer the family variant test to siblings, parents and children -testing children is appropriate because cardiac screening and lifestyle advice in childhood can change management.
• Relatives who test negative can stop cardiac surveillance; those positive need regular ECG and echo.
• Provide a family letter; refer to the inherited cardiac conditions service.

5. A woman's mother had a pathogenic MLH1 variant. She tests negative for it. She asks whether she still needs colonoscopy.
Answer: True negative -her risk is now that of the general population.

• She doesn't need Lynch syndrome surveillance; national bowel screening as for the general population.
• Her children aren't at risk from this variant.
• Explain clearly in a letter; support for any "survivor guilt".

Key Points

• The NHS Genomic Medicine Service and National Genomic Test Directory set who can be tested, for what and by whom.
• Karyotype detects balanced rearrangements; microarray detects small copy number changes but not balanced ones.
• QF-PCR gives a rapid trisomy result.
• Microarray or genome sequencing is first line for developmental delay and multiple anomalies.
• NGS (panels, exome, genome) may miss repeat expansions -test fragile X, Huntington's and myotonic dystrophy specifically.
• MLPA for exon deletions (DMD, SMA); methylation tests for imprinting disorders.
• Variants are classified 1–5; a VUS is not actionable.
• A negative result is only "true negative" when the family variant is known.
• Consent covers implications for relatives and incidental findings.
• Defer predictive testing of children for adult-onset conditions with no childhood intervention.
• Cascade testing finds at-risk relatives -support with a family letter.

Guidelines and Further Reading

• NHS England: National Genomic Test Directory (rare and inherited disease; cancer)
• Royal College of Physicians, Royal College of Pathologists and British Society for Genetic Medicine: Consent and confidentiality in genomic medicine (2019)
• Association for Clinical Genomic Science (ACGS): Best practice guidelines for variant classification
• British Society for Genetic Medicine: Genetic testing of children
• Health Education England Genomics Education Programme: GeNotes
• RCOG Green-top Guideline 17: Recurrent miscarriage
• BNF -for current doses