Clinical Genetics: Prenatal and newborn screening, pharmacogenomics and ethics

• Antenatal: Antenatal Genetic Screening - Overview | Screening for Down, Edwards and Patau Syndromes | Non-invasive Prenatal Testing (NIPT) | The Fetal Anomaly Scan and Fetal Anomalies | Sickle Cell and Thalassaemia Screening | Prenatal Diagnosis - CVS and Amniocentesis | Reproductive Options - PGT and Mitochondrial Donation
• Newborn and population: Newborn Blood Spot Screening | Other Newborn Screening and Genome Sequencing | Carrier Screening and Consanguinity
• Pharmacogenomics: Pharmacogenomics - Principles | Pharmacogenomic Tests in Practice | Inherited Anaesthetic Reactions
• Ethics and law: Consent and Confidentiality in Genetics | Disclosure to Relatives | Insurance, Employment and the Law
• Revision: Screening and Pharmacogenomics at a Glance | Spot the Diagnosis | Exam-style Scenarios | Key Points | Guidelines and Further Reading

🧬 Prenatal and newborn screening, pharmacogenomics and ethics - page 6 of the Clinical Genetics chapter. Every pregnant woman in the UK is offered genetic screening, and every newborn has a blood spot test - so all doctors need to explain these tests and their results. Pharmacogenomics is now part of everyday prescribing (DPYD before capecitabine, HLA-B*57:01 before abacavir, CYP2C19 before clopidogrel after stroke). And because genetic information is shared within families, it raises particular questions about consent, confidentiality and insurance.
Your four questions for every screening or pharmacogenomic test: Is this a screening test or a diagnostic test? What will a "higher chance" or positive result mean, and what happens next? Has the person made an informed, voluntary choice? Who else does the result affect?

Antenatal Genetic Screening - Overview

• NHS antenatal screening programmes (England) - offered, not compulsory; informed choice at the booking appointment (ideally before 10 weeks).
• Genetic and fetal conditions screened:
  • Sickle cell disease and thalassaemia - offered by 10 weeks.
  • Down, Edwards and Patau syndromes - combined test (or quadruple test later).
  • Fetal anomaly scan at 18+0 to 20+6 weeks - 11 serious physical conditions.
• Also infectious diseases (HIV, hepatitis B, syphilis), blood group and antibodies, diabetes risk, and newborn and infant screening after birth.
• Screening vs diagnosis - screening identifies a "higher chance" (not a diagnosis) and is followed by an offer of diagnostic testing; diagnostic tests (CVS, amniocentesis) give a definite answer but carry a small miscarriage risk.
• Language - NHS uses "higher chance" and "lower chance" rather than "high risk" - non-directive, balanced information, including about life with the condition.
• Termination of pregnancy - under the Abortion Act 1967, ground E allows termination at any gestation where there is a substantial risk of serious physical or mental abnormality; decisions are the woman's, supported by fetal medicine and counselling.

Screening for Down, Edwards and Patau Syndromes

• Combined test (first line) - 10+0 to 14+1 weeks (crown–rump length 45–84 mm):
  • Nuchal translucency (ultrasound) + free beta-hCG + PAPP-A + maternal age.
  • Down syndrome - raised NT, high beta-hCG, low PAPP-A.
  • Edwards and Patau - raised NT, low beta-hCG, low PAPP-A.
  • Detection about 85% for Down syndrome with about a 2–3% screen-positive rate.
• Quadruple test - 14+2 to 20+0 weeks (if presenting late or NT can't be measured) - Down syndrome only:
  • AFP low, unconjugated oestriol low, hCG high, inhibin-A high.
  • Detection about 80%.
• Result - "higher chance" if the chance is 1 in 150 or greater at term.
• After a higher chance result, the woman chooses between:
  1. NIPT (second-line screening - no miscarriage risk).
  2. Diagnostic test (CVS or amniocentesis).
  3. No further testing.
• Raised nuchal translucency (3.5 mm or more) with a normal karyotype - still associated with heart defects and other syndromes (e.g. Noonan syndrome) - offer fetal echocardiography and further testing.
• Other markers - raised maternal serum AFP suggests open neural tube defects or abdominal wall defects (now mainly detected by ultrasound).

Non-invasive Prenatal Testing (NIPT)

• Cell-free DNA in maternal blood - about 10% comes from the placenta (the "fetal fraction"); counted to detect aneuploidy.
• NHS use - offered as a contingent second-line screen after a higher chance combined or quadruple result (since 2021); available privately as first-line screening.
• Performance - detects about 99% of Down syndrome; lower for Edwards and Patau; very low false-positive rate - but still a screening test.
• A "higher chance" NIPT result must be confirmed by CVS or amniocentesis before any irreversible decision - false positives occur from confined placental mosaicism, a vanishing twin, maternal chromosomal anomalies or maternal cancer.
• Failed tests - low fetal fraction (higher maternal BMI, early gestation); a repeat may be offered; a failed result is itself associated with aneuploidy.
• Other uses - fetal sex (for X-linked conditions - e.g. DMD, haemophilia - avoids invasive tests in female fetuses), fetal RhD genotyping (targets anti-D prophylaxis to RhD-negative women carrying RhD-positive babies), and specific single-gene tests (e.g. achondroplasia, or a paternally inherited variant) in specialist centres.
• Ethical issues - informed choice, routinisation, impact on the disability community, private tests reporting many more conditions.

The Fetal Anomaly Scan and Fetal Anomalies

• Mid-pregnancy scan - 18+0 to 20+6 weeks (NHS Fetal Anomaly Screening Programme) - screens for 11 conditions: anencephaly, open spina bifida, cleft lip, congenital diaphragmatic hernia, gastroschisis, exomphalos, serious cardiac anomalies, bilateral renal agenesis, lethal skeletal dysplasia, Edwards syndrome and Patau syndrome.
• Soft markers (e.g. echogenic bowel, mild ventriculomegaly, choroid plexus cysts) - often normal variants; significance depends on context.
• Genetic associations to know:
  • Exomphalos - associated with chromosomal anomalies (trisomy 18, 13) and Beckwith–Wiedemann; gastroschisis - usually isolated (young mothers, not genetic).
  • Duodenal atresia ("double bubble") - Down syndrome in about 30%.
  • Cystic hygroma and hydrops - Turner syndrome, Noonan syndrome, trisomies.
  • Conotruncal heart defects - 22q11.2 deletion.
  • Holoprosencephaly - trisomy 13.
  • Short long bones - skeletal dysplasias (achondroplasia - FGFR3; thanatophoric dysplasia - lethal).
• After an anomaly is found - urgent fetal medicine referral (within 3 working days for most); QF-PCR then microarray (or rapid exome sequencing - NHS prenatal exome service for anomalies suggestive of a monogenic disorder) on CVS or amniocentesis samples; counselling about prognosis, treatment and options.

Sickle Cell and Thalassaemia Screening

• NHS Sickle Cell and Thalassaemia Screening Programme - offered to all pregnant women by 10 weeks:
  • High-prevalence areas - laboratory screening (haemoglobin HPLC) for all women.
  • Low-prevalence areas - Family Origin Questionnaire for all; laboratory screening for those at higher risk; all women screened for thalassaemia via red cell indices (MCH under 27 pg prompts further testing).
• If the woman is a carrier - offer testing of the baby's biological father promptly.
• If both are carriers (e.g. HbAS and HbAS - 1 in 4 chance of HbSS; or HbAS and beta-thalassaemia trait - 1 in 4 HbS/beta-thal) - counselling and prenatal diagnosis (ideally by 12+6 weeks - CVS).
• Iron deficiency can mask beta-thalassaemia trait (HbA2 may be lowered) - interpret with ferritin.
• Newborn screening - all babies screened for sickle cell disease on the blood spot.
• Preconception carrier testing - offered via GP or specialist services for couples of at-risk ancestry or with a family history.

Prenatal Diagnosis - CVS and Amniocentesis

• Tests on the sample - QF-PCR (rapid aneuploidy - 1–3 days), microarray (if an anomaly is seen), targeted gene test for a known family variant, rapid prenatal exome.
• Anti-D for RhD-negative women after the procedure (unless the fetus is known to be RhD-negative).
• Other risks - infection, amniotic fluid leakage; check HIV, hepatitis B and C status beforehand (vertical transmission risk).
• Fetal blood sampling (cordocentesis) - rarely; for fetal anaemia and transfusion.

Reproductive Options - PGT and Mitochondrial Donation

• Options for at-risk couples - natural conception (with or without prenatal diagnosis), preimplantation genetic testing, donor eggs or sperm, adoption, choosing not to have children.
• Preimplantation genetic testing for monogenic disorders (PGT-M) - IVF; cells biopsied from embryos and tested; only unaffected embryos transferred.
  • Regulated by the HFEA - only for conditions approved on the HFEA list (e.g. CF, Huntington's, BRCA, DMD, sickle cell disease).
  • PGT-SR for structural chromosomal rearrangements (balanced translocation carriers).
  • NHS funding - eligibility criteria apply (e.g. no unaffected living child).
  • Exclusion testing - for Huntington's disease when the at-risk parent doesn't want to know their own status.
• PGT-A (aneuploidy screening) - used privately in IVF; the HFEA rates evidence of benefit as weak ("red" add-on).
• Sex selection for non-medical reasons is illegal in the UK; selection is allowed to avoid a serious sex-linked condition.
• Saviour siblings - PGT with HLA tissue typing is permitted by the HFEA to select an embryo that could donate cord blood or bone marrow to an affected sibling.
• Mitochondrial donation (pronuclear transfer) - legal in the UK since 2015 (Human Fertilisation and Embryology Regulations); licensed at Newcastle to prevent serious mitochondrial DNA disease - babies born healthy have been reported.
• Germline genome editing for reproduction is illegal in the UK.

Newborn Blood Spot Screening

• Heel prick blood spot at about day 5 (day of birth is day 0; between day 5 and day 8).
• Nine conditions (England):

  Condition	Why screen - early treatment
  Sickle cell disease	Penicillin prophylaxis, vaccines, parental education - prevents pneumococcal deaths
  Cystic fibrosis	Early nutrition, enzymes and physiotherapy - better growth and lungs
  Congenital hypothyroidism	Levothyroxine within 2–3 weeks prevents learning disability
  Phenylketonuria	Low-phenylalanine diet prevents learning disability
  MCADD	Avoiding fasting and an emergency plan prevent hypoglycaemic death
  Maple syrup urine disease	Diet prevents encephalopathy
  Isovaleric acidaemia	Diet and emergency plan
  Glutaric aciduria type 1	Diet prevents brain damage (dystonia)
  Homocystinuria (pyridoxine unresponsive)	Diet prevents lens dislocation, learning disability and thrombosis

• Also detected - carriers of sickle cell (parents informed - implications for future pregnancies); some CF carriers.
• Under evaluation - SCID (severe combined immunodeficiency) in-service evaluation in parts of England; the UK National Screening Committee keeps the list under review (e.g. SMA, tyrosinaemia).
• Consent - parents can decline; samples are stored and may be used for quality assurance or (with consent) research.
• Repeat sample if premature, transfused or results unclear.
• The UK nations differ slightly in the conditions screened.

Other Newborn Screening and Genome Sequencing

• Newborn and infant physical examination (NIPE) - within 72 hours and again at 6–8 weeks - eyes (red reflex - congenital cataract, retinoblastoma), heart (congenital heart disease), hips (developmental dysplasia - ultrasound if risk factors such as breech or family history), testes (undescended).
• Newborn hearing screening - automated otoacoustic emissions or auditory brainstem response - about half of congenital hearing loss is genetic (GJB2 - connexin 26 - commonest; also syndromes - Pendred, Usher, Waardenburg, Jervell and Lange-Nielsen - check ECG in congenitally deaf children).
• Congenital CMV - a major non-genetic cause of hearing loss - test within 21 days if hearing screening is failed.
• The Generation Study (Genomics England and NHS England) - research study offering whole genome sequencing to newborns to look for over 200 rare, treatable childhood-onset conditions; raises questions about consent, uncertain results, storage and future use of genomic data.
• Rapid genome sequencing for critically ill infants (see page 2).

Carrier Screening and Consanguinity

• Consanguinity - a relationship between people who share a common ancestor (most often first cousins); common in some communities in the UK and worldwide.
• Risk - first-cousin couples have about a doubling of the background risk of a child with a serious congenital or recessive condition (about 4–6% vs 2–3%) - most children are healthy.
• Approach - sensitive, non-judgemental discussion; family history of recessive conditions; targeted carrier testing for known family conditions; genetic counselling; avoid stigmatising communities.
• Population carrier screening:
  • Haemoglobinopathies - national antenatal programme.
  • Tay–Sachs and other conditions in the Jewish community - community-led premarital and preconception screening programmes (e.g. Ashkenazi carrier panels).
  • Expanded carrier screening (hundreds of recessive genes) - offered privately; not part of NHS routine care.
• Cousin marriage is legal in the UK; advice is about informed reproductive choice, not discouraging relationships.

Pharmacogenomics - Principles

• Pharmacogenomics - how genetic variation affects drug response - efficacy and adverse reactions.
• Mechanisms:
  • Pharmacokinetic - variants in drug-metabolising enzymes (CYP2D6, CYP2C19, CYP2C9, TPMT, NUDT15, DPYD, UGT1A1) - poor, intermediate, normal, rapid and ultrarapid metabolisers.
  • Pharmacodynamic - variants in drug targets (VKORC1 - warfarin sensitivity).
  • Immune-mediated - HLA alleles predisposing to severe hypersensitivity (SJS/TEN, DRESS, drug-induced liver injury).
  • Mitochondrial - MT-RNR1 (aminoglycoside ototoxicity).
• Prodrugs - poor metabolisers get less effect (codeine → morphine; clopidogrel → active metabolite; tamoxifen → endoxifen); ultrarapid metabolisers get more effect or toxicity (codeine - morphine toxicity).
• Ancestry matters - e.g. HLA-B*15:02 is common in South-East Asian populations; CYP2C19 poor metabolisers are more common in East Asian populations; CYP2D6 ultrarapid metabolisers are more common in North African and Middle Eastern populations.
• Implementation - a few tests are standard before prescribing in the NHS; pre-emptive panel testing is being piloted; results should be recorded in the patient's record for future prescribing.
• Interactions can mimic genotype (phenoconversion) - e.g. fluoxetine or paroxetine (CYP2D6 inhibitors) make a normal metaboliser behave like a poor metaboliser.

Pharmacogenomic Tests in Practice

Inherited Anaesthetic Reactions

• Malignant hyperthermia - autosomal dominant (RYR1, CACNA1S) - triggered by volatile anaesthetics (sevoflurane, desflurane, isoflurane) and suxamethonium.
  • Features - rising end-tidal CO₂, tachycardia, muscle rigidity (masseter spasm), hyperthermia (late), metabolic and respiratory acidosis, hyperkalaemia, rhabdomyolysis, arrhythmias.
  • Treatment - stop triggers, hyperventilate with 100% oxygen, IV dantrolene, active cooling, treat hyperkalaemia.
  • Family - refer the patient and relatives to the UK MH Investigation Unit (Leeds) for muscle biopsy (in vitro contracture test) or genetic testing; "trigger-free" anaesthesia for those at risk; MedicAlert.
  • Associated with central core disease and some other myopathies.
• Butyrylcholinesterase (pseudocholinesterase) deficiency - autosomal recessive (BCHE) - prolonged paralysis and apnoea after suxamethonium or mivacurium - ventilate and sedate until recovery; test the patient and family; alert card.
• Other genetic conditions with anaesthetic risk - myotonic dystrophy and Duchenne (suxamethonium and volatiles), porphyria (avoid barbiturates and some drugs - use a safe drug list), Down syndrome (atlantoaxial instability), Marfan and vascular EDS, long QT and Brugada (drug choices).

Consent and Confidentiality in Genetics

• Valid consent (Montgomery, GMC) - the person must understand:
  • The purpose of the test, what it can and can't find, and the possible results (positive, negative, uncertain, incidental).
  • Implications for relatives - and the expectation that results may be shared to help family members.
  • Storage of the sample and data, and possible use for research (e.g. National Genomic Research Library).
  • Implications for insurance and employment.
• Record of discussion forms are used for NHS genomic tests.
• Capacity - for adults who lack capacity, testing can be done in their best interests under the Mental Capacity Act 2005 (e.g. to diagnose a condition, or where the result would benefit the family with little burden to the person).
• Children - test when the result helps the child's health now; defer adult-onset predictive testing (see page 2).
• Human Tissue Act 2004 - it is a criminal offence to analyse someone's DNA without consent (e.g. covert paternity testing on stolen samples), with specific exceptions (e.g. medical diagnosis or treatment, coroner's work).
• Confidentiality - genetic information is confidential to the patient, but is "familial" - it reveals information about relatives too.

Disclosure to Relatives

• First approach - encourage and support the patient to tell their relatives (family letter, help from clinical genetics).
• If the patient refuses - explore reasons, give time, explain the benefits to relatives.
• GMC guidance (Confidentiality, 2017) - disclosure without consent may be justified in the public interest if the risk of serious harm to a relative outweighs the patient's interest in confidentiality, particularly where effective prevention or treatment is available; tell the patient beforehand where practicable; disclose only the minimum necessary information; seek advice (Caldicott guardian, defence body, clinical ethics).
• ABC v St George's Healthcare NHS Trust (2020) - a woman's father had Huntington's disease and refused to let her be told; she was pregnant. The High Court held that clinicians have a legal duty to consider and balance the interests of a relative in learning genetic information, though on the facts the claim failed. Doctors must weigh the issue and document their reasoning - not simply ignore relatives.
• Joint account model (RCP/RCPath/BSGM) - genetic information may be seen as shared by the family; the clinician's use of a familial variant result to test a relative doesn't usually breach confidentiality if personal details aren't revealed.
• Non-disclosure of misattributed parentage - usually not revealed unless essential to the clinical question.

💡 Clinical Pearl: When a patient won't share a serious, preventable genetic risk with relatives, don't decide alone and don't ignore it. Explore their reasons, revisit the conversation, take advice and record how you balanced the patient's confidentiality against the relatives' risk of harm.

Insurance, Employment and the Law

• Code on Genetic Testing and Insurance (UK Government and Association of British Insurers, 2018 - voluntary, open-ended, reviewed every 3 years):
  • Insurers cannot require or pressure anyone to take a predictive or diagnostic genetic test.
  • Insurers cannot ask for or use the results of predictive genetic tests - with one exception: Huntington's disease for life insurance over £500,000.
  • Insurers can ask about diagnostic test results (a confirmed diagnosis) and family history.
  • Results from research participation don't need to be disclosed.
• Employment - no specific UK genetic discrimination law; the Equality Act 2010 protects people with disabilities (including some genetic conditions once symptomatic); employers shouldn't request genetic tests.
• Driving - tell the DVLA about conditions affecting driving (e.g. Huntington's with symptoms, inherited arrhythmias after syncope or ICD, epilepsy) - not about predictive results alone.
• Human Fertilisation and Embryology Act - regulates PGT, embryo research and mitochondrial donation; prohibits non-medical sex selection and reproductive germline editing.
• Genomic data - UK GDPR classifies genetic data as special category data; NHS genomic data in research is held securely (Genomics England National Genomic Research Library) with consent.
• Equity - genomic reference data are mostly from people of European ancestry - higher VUS rates and less accurate risk prediction in other groups; NHS efforts aim to improve diversity.

Screening and Pharmacogenomics at a Glance

Spot the Diagnosis

Exam-style Scenarios

1. A 37-year-old woman's combined test shows a 1 in 40 chance of Down syndrome. She asks what to do.
Answer: Higher chance result - offer informed choice of next steps.

• Options - NIPT (no miscarriage risk, about 99% detection but still screening), CVS (diagnostic, now) or amniocentesis (from 15 weeks), or no further testing.
• Explain that a higher chance NIPT result needs confirmation by an invasive test before any decision about the pregnancy.
• Non-directive counselling with balanced information about Down syndrome; support organisations (e.g. Antenatal Results and Choices).