Clinical Genetics: Inherited Conditions and Genomic Testing

Genetics and Genomics, Lecture 3. This lecture covers the clinical application of genetics — inheritance patterns, chromosomal and copy-number disorders, hereditary cancer syndromes, pharmacogenomics, and genetic counselling.

PATTERNS OF INHERITANCE

Autosomal dominant (AD): one mutant allele sufficient to cause disease. Each offspring of an affected parent has a 50% risk of inheriting the mutation. Key features: variable expressivity (phenotype varies among carriers), reduced penetrance (some carriers show no phenotype), and de novo mutations (new mutations not inherited from either parent — important for achondroplasia where >95% are de novo). Classic examples: achondroplasia (FGFR3 p.Gly380Arg gain-of-function — constitutively active fibroblast growth factor receptor impairs endochondral ossification); Marfan syndrome (FBN1 loss-of-function — fibrillin-1 deficiency weakens connective tissue, causing aortic root dilatation, lens dislocation, tall stature); familial hypercholesterolaemia (LDLR — LDL receptor loss-of-function, markedly elevated LDL from birth, premature coronary artery disease); Huntington disease (HTT CAG repeat expansion >40 causes toxic polyglutamine tract in huntingtin protein — autosomal dominant, full penetrance at >40 repeats, anticipation through paternal transmission).

Autosomal recessive (AR): two mutant alleles required (homozygous or compound heterozygous). Risk when both parents are carriers: 25% affected, 50% carrier, 25% unaffected. Consanguinity (related parents) raises the prior probability of sharing recessive alleles, increasing risk. Major categories: enzyme deficiencies — phenylketonuria (PKU: PAH gene; phenylalanine hydroxylase deficiency; treated by phenylalanine-restricted diet + BH4 supplementation in some); cystic fibrosis (CFTR: delta-F508 most common in Europeans — deletion of phenylalanine-508 causes misfolding and ER retention of the CFTR chloride channel; leads to thick mucus in airways, pancreatic exocrine insufficiency, infertility in males); spinal muscular atrophy (SMA: SMN1 deletion — deficiency of survival motor neuron protein causes lower motor neuron degeneration; treated by nusinersen or gene therapy onasemnogene abeparvovec).

X-linked recessive: males (hemizygous XY) are affected; carrier females are usually unaffected but may show mild features due to skewed lyonisation (X-inactivation). No male-to-male transmission. Lyonisation: random X-inactivation in females; if skewed toward inactivating the normal X, carrier females may be symptomatic. Examples: Duchenne muscular dystrophy (DMD: dystrophin frameshift — absent dystrophin causes progressive muscle fibre necrosis; raised CK, Gowers sign, cardiomyopathy); haemophilia A (FVIII deficiency — X-linked, carrier females have ~50% factor levels but are rarely symptomatic).

CHROMOSOMAL DISORDERS

Trisomy 21 (Down syndrome, 47,+21): intellectual disability (mild to moderate), characteristic facies, hypotonia, cardiac defects (ASD, VSD, atrioventricular septal defect AVSD in ~50%), duodenal atresia, hypothyroidism, increased Alzheimer risk (APP on chromosome 21). Arises by non-disjunction in meiosis I (most commonly maternal); risk rises sharply with advanced maternal age.

Trisomy 18 (Edwards syndrome, 47,+18): severe — clenched fists, rocker-bottom feet, micrognathia, cardiac and renal defects; most die within days to weeks. Trisomy 13 (Patau syndrome, 47,+13): holoprosencephaly, midline facial defects, polydactyly; poor prognosis.

Sex chromosome aneuploidies: Turner syndrome (45,X): short stature, ovarian dysgenesis (streak gonads, primary amenorrhoea), coarctation of the aorta, webbed neck, lymphoedema. Klinefelter syndrome (47,XXY): most common sex chromosome aneuploidy in males; tall stature, small firm testes, infertility (azoospermia), gynaecomastia, reduced facial hair, mildly reduced verbal IQ. Non-disjunction mechanism: failure of chromosomes to separate correctly at meiosis I or II, or (for sex chromosome errors) at post-zygotic mitosis.

COPY NUMBER VARIANTS (CNVs)

22q11.2 deletion syndrome (DiGeorge/velocardiofacial): conotruncal heart defects (tetralogy of Fallot, truncus arteriosus, interrupted aortic arch), hypocalcaemia (absent/hypoplastic parathyroids), immune deficiency (absent/hypoplastic thymus and T-cell lymphopenia), palatal abnormalities (velopharyngeal insufficiency, cleft palate), learning difficulties, psychiatric risk (schizophrenia ~25%). Most are de novo deletions. Williams syndrome (7q11.23 deletion): deletion of ELN (elastin) and other genes; supravalvular aortic stenosis, hypercalcaemia, "elfin" facies, intellectual disability with strong verbal and social skills ("cocktail party" personality).

Imprinting disorders: genomic imprinting is the epigenetic silencing of one parental allele. Prader-Willi syndrome and Angelman syndrome both involve the chromosome 15q11-13 region but differ based on parental origin. Prader-Willi: loss of paternally expressed genes in 15q11-13 (deletion of paternal chromosome 15, or maternal uniparental disomy — both chromosome 15s from mother); features: neonatal hypotonia, hyperphagia, obesity, short stature, hypogonadism, mild intellectual disability. Angelman syndrome: loss of maternally expressed UBE3A (deletion of maternal chromosome 15, or paternal uniparental disomy); features: severe intellectual disability, absent speech, seizures, ataxic gait, happy affect.

HEREDITARY CANCER SYNDROMES

BRCA1/BRCA2 (hereditary breast and ovarian cancer): autosomal dominant inheritance; BRCA1 and BRCA2 are tumour suppressor genes involved in homologous recombination DNA repair. BRCA1 pathogenic variants: ~70% lifetime breast cancer risk, ~40% ovarian cancer risk. BRCA2: similar breast cancer risk, lower ovarian risk but increased risk of male breast cancer and pancreatic cancer. Management options: enhanced surveillance (annual MRI + mammogram), risk-reducing bilateral salpingo-oophorectomy (RRBSO), risk-reducing mastectomy. BRCA-deficient cancers have synthetic lethality with PARP inhibitors (olaparib) — used in treatment of advanced ovarian and breast cancers with BRCA mutations.

Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC): autosomal dominant; caused by germline pathogenic variants in DNA mismatch repair genes MLH1, MSH2, MSH6, or PMS2. Tumours show microsatellite instability (MSI-high). Amsterdam criteria II: three relatives with Lynch-associated cancer (colorectal, endometrial, ovarian, ureter/renal pelvis, small bowel, biliary) spanning two generations, one being a first-degree relative of the other two, and one diagnosed under age 50. Colorectal cancer risk ~40-80% (depending on gene); endometrial cancer risk up to 60%. Surveillance: annual colonoscopy; endometrial sampling.

PHARMACOGENOMICS

CYP2D6: metabolises ~25% of clinical drugs. Poor metabolisers (PMs) — no functional enzyme (e.g., *4/*4 alleles): cannot convert codeine to morphine (codeine is a prodrug); reduced analgesia with codeine; tramadol also less effective. Ultra-rapid metabolisers (UMs) — multiple copies of functional allele: convert codeine to toxic morphine levels rapidly; risk of morphine overdose, particularly dangerous in breastfed infants of UM mothers. Clinical recommendation: avoid codeine in UMs; offer alternative opioid. Also relevant for tamoxifen (requires CYP2D6 conversion to active endoxifen) and antidepressants (TCAs, some SSRIs).

CYP2C19: relevant for clopidogrel activation (prodrug requiring CYP2C19); poor metabolisers have reduced antiplatelet effect — associated with worse cardiovascular outcomes post-PCI; ultra-rapid metabolisers may have increased bleeding risk. CYP2C19 also metabolises PPIs (poor metabolisers have higher PPI exposure — more effective acid suppression) and some antidepressants.

HLA-B*5701: strongly associated with abacavir hypersensitivity reaction (AHR) — fever, rash, GI symptoms, potentially fatal on re-exposure. Prospective HLA-B*5701 screening before prescribing abacavir has virtually eliminated AHR in clinical practice.

TPMT (thiopurine S-methyltransferase) and NUDT15: both relevant to azathioprine and 6-mercaptopurine toxicity. TPMT poor metabolisers accumulate active thioguanine nucleotides — severe bone marrow suppression risk. NUDT15 variants (more prevalent in East Asian and Hispanic populations) similarly predict toxicity. Testing before prescribing reduces haematological toxicity.

GENETIC COUNSELLING PRINCIPLES

Genetic counselling is a communication process helping individuals and families understand genetic conditions and their implications. Principles: non-directive counselling (clinician provides information and support without directing the patient's decision); informed consent for predictive testing (pre-test counselling about implications of positive and negative results, psychological impact, insurance and employment considerations, implications for relatives); pre-test and post-test support. Duty to warn third parties: genetic information has implications for biologically related family members. Ethical tension arises between the clinician's duty of confidentiality to the index patient and the potential duty to warn relatives who may benefit from cascade testing. Most guidelines recommend supporting the patient to disclose, but acknowledge limited circumstances where disclosure to identifiable at-risk relatives may be warranted without patient consent.