Clinical Genetics & Genetic Counselling

Genetics and Genomics, Lecture 5. This lecture covers inheritance patterns, clinical genetic conditions, genetic counselling principles, and prenatal diagnosis — with attention to the Aotearoa New Zealand clinical and cultural context including Māori and Pacific perspectives.

PATTERNS OF INHERITANCE

Autosomal dominant (AD): a single mutant allele on one of the autosomes (non-sex chromosomes) is sufficient to cause disease. Each affected individual has a 50% chance of transmitting the disease allele to each offspring, regardless of offspring sex. Key features: (1) Variable expressivity — the severity of phenotype varies between individuals who carry the same pathogenic variant, due to modifier genes, environmental factors, and stochastic effects. Example: NF1 (neurofibromatosis type 1): one person may have only café-au-lait macules, another from the same family may have plexiform neurofibromas and optic glioma. (2) Reduced penetrance — a proportion of individuals who carry the pathogenic variant do not manifest the phenotype at all. Example: BRCA2 — lifetime penetrance for breast cancer is ~55-70%, meaning not all BRCA2 carriers develop breast cancer. (3) De novo mutations — many severe AD conditions arise from new (de novo) mutations in the germline, not inherited from an affected parent. Example: achondroplasia (FGFR3 Gly380Arg) — >95% are de novo. This means parents of an affected child may be unaffected, but the recurrence risk for future siblings is very low (gonadal mosaicism risk approximately 1%).

Major AD conditions: Huntington disease (HTT CAG repeat expansion >36 — see trinucleotide repeats below); Marfan syndrome (FBN1 — fibrillin-1, aortic root dilatation, lens dislocation, tall stature); familial hypercholesterolaemia (LDLR — 1 in 250 people in New Zealand; premature coronary artery disease; heterozygous LDL typically 5-10 mmol/L); BRCA1/2 (hereditary breast and ovarian cancer syndrome — see Lesson 4 for cancer surveillance details); NF1/NF2 (neurofibromatosis); tuberous sclerosis (TSC1/TSC2 — hamartomas in brain, kidney, skin, lung).

Anticipation in trinucleotide repeat disorders: anticipation describes the phenomenon of a genetic disorder becoming more severe and/or presenting at earlier age in successive generations. This occurs in diseases caused by unstable trinucleotide repeat expansions, where the repeat length increases during meiosis (particularly in paternal transmission for Huntington disease, and maternal for myotonic dystrophy). Huntington disease (HD): CAG repeat in HTT exon 1 (polyglutamine); normal ≤35 repeats; reduced penetrance 36-39; full penetrance ≥40. Symptoms typically begin 35-50 years for 40-50 repeats; juvenile onset (<20 yrs) with very large expansions (>60) paternally inherited. Myotonic dystrophy type 1 (DM1): CTG repeat in DMPK 3'UTR; normal <35; mildly affected >50; severely affected >100; congenital form >1000 repeats (exclusively maternally transmitted); anticipation through maternal meiosis. Fragile X syndrome (FMRI CGG repeat): premutation 55-200 repeats; full mutation >200 repeats; X-linked (not AD); premutation carriers (especially women) at risk of fragile X-associated tremor/ataxia syndrome (FXTAS) and premature ovarian insufficiency; expansion occurs through maternal meiosis.

Autosomal recessive (AR): two pathogenic alleles (homozygous or compound heterozygous) are required to cause disease. If both parents are carriers (heterozygous): 25% of offspring are affected (homozygous mutant), 50% are carriers (unaffected), and 25% are homozygous normal. Consanguinity — relatedness between parents — increases the prior probability that both parents share the same recessive allele inherited from a common ancestor. The coefficient of relationship (r) for first cousins is 1/8; their offspring have an approximately 2-fold increased risk of autosomal recessive disease overall. Carrier frequency in a population determines disease frequency: by Hardy-Weinberg, disease frequency q² = (carrier frequency/2)². In NZ: cystic fibrosis carrier frequency approximately 1 in 25 in Europeans (disease frequency ~1 in 2500); spinal muscular atrophy carrier frequency approximately 1 in 35 (Pan-ethnic); haemochromatosis (HFE C282Y) carrier frequency approximately 1 in 8 in northern European ancestry; sickle cell disease carrier (HbAS) frequency approximately 1 in 4 in West African ancestry populations — relevant to NZ Pacific communities.

AR examples: cystic fibrosis (CFTR — p.Phe508del most common in Europeans); PKU (PAH); SMA (SMN1 deletion); haemochromatosis (HFE C282Y/H63D — autosomal recessive but common polymorphism, incomplete penetrance); Wilson disease (ATP7B — copper overload); Gaucher disease (GBA — lysosomal storage disorder).

X-linked recessive: the gene is on the X chromosome. Males (XY, hemizygous) are affected by a single mutant X allele because they have no second X to compensate. Carrier females (heterozygous XX) are usually unaffected because the normal allele on the second X provides sufficient gene product; however, due to skewed X-inactivation (Lyon effect), some carrier females manifest mild to moderate disease features (manifesting carriers). Pattern: no male-to-male transmission (fathers pass their Y to sons); all daughters of an affected male are obligate carriers; sons of a carrier female have a 50% chance of being affected; daughters of a carrier female have a 50% chance of being carriers.

G6PD deficiency — Pacific context: G6PD (glucose-6-phosphate dehydrogenase) deficiency is the most common enzymopathy worldwide, affecting approximately 400 million people. X-linked recessive. G6PD protects red blood cells from oxidative haemolysis; deficiency causes acute haemolytic anaemia when triggered by oxidative stress: infections, fava beans, oxidant drugs (primaquine, rasburicase, dapsone, high-dose aspirin). Prevalence in NZ: elevated in Samoan, Tongan, Niuean, and other Pacific peoples (reflecting origins in malaria-endemic regions where G6PD deficiency confers survival advantage against P. falciparum). Clinically important: before prescribing primaquine (for malaria relapse prevention — P. vivax, P. ovale), G6PD status must be tested. Haemolytic risk also relevant with rasburicase (uric acid treatment in tumour lysis syndrome) — contraindicated in G6PD deficiency.

Other XLR examples: haemophilia A (FVIII) and B (FIX); Duchenne/Becker muscular dystrophy (DMD — dystrophin frameshift/missense); X-linked agammaglobulinaemia (BTK); colour vision deficiency (OPN1MW/LW — affects approximately 8% of males in New Zealand).

X-linked dominant (XLD): rare; one mutant allele on the X chromosome is sufficient for disease in both males and females. Males may be more severely affected (hemizygous). Examples: Rett syndrome (MECP2 — severe in males, typically lethal prenatally; heterozygous females develop progressive neurological regression, stereotyped hand movements, and respiratory irregularity); hypophosphataemic rickets (PHEX); incontinentia pigmenti (IKBKG — lethal in hemizygous males; females have skin, dental, and neurological features).

Mitochondrial inheritance: mitochondria contain their own circular 16.6 kb genome encoding 13 OXPHOS proteins, 22 tRNAs, and 2 rRNAs. Mitochondrial DNA (mtDNA) is inherited almost exclusively from the mother (a fertilised egg contains thousands of mitochondria from the oocyte, vastly outnumbering the few mitochondria contributed by the sperm tail). Key features: maternal-only inheritance — all children of an affected mother are at risk; no paternal transmission. Heteroplasmy — a single cell may contain a mixture of normal and mutant mtDNA; the proportion of mutant mtDNA determines phenotypic severity. Threshold effect — clinical features typically emerge only when the proportion of mutant mtDNA in affected tissues exceeds a threshold (often 60-90%). MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes): most commonly caused by m.3243A>G variant in MT-TL1 (mitochondrial tRNA-Leu gene); presents with stroke-like episodes in young people, seizures, lactic acidosis, diabetes, sensorineural deafness. Leber hereditary optic neuropathy (LHON): caused by variants in MT-ND1/4/6 (NADH dehydrogenase subunits); predominantly affects young males (unclear male predominance; may involve X-linked modifier); acute painless central vision loss, often bilateral.

Genomic imprinting: see also Lesson 3 (chromosomal). The same region of chromosome 15q11-13 causes two completely different syndromes depending on parental origin. Prader-Willi syndrome (PWS): loss of paternally expressed genes in 15q11-13. Mechanism: deletion of paternal 15q11-13 (~70%); maternal uniparental disomy (UPD(15)mat — both copies of chromosome 15 from mother; ~25%); imprinting centre defect (~5%). Features: neonatal hypotonia and feeding difficulty; hyperphagia and obesity from early childhood; short stature; hypogonadism; mild intellectual disability. Angelman syndrome (AS): loss of maternally expressed UBE3A in 15q11-13. Mechanism: deletion of maternal 15q11-13 (~70%); paternal UPD(15)pat (~7%); imprinting centre defect; UBE3A pathogenic variant. Features: severe intellectual disability; absent speech; seizures (characteristic EEG); ataxic gait; happy, sociable demeanour; hypopigmentation (when deletion involves OCA2 gene).

GENETIC COUNSELLING PRINCIPLES

Genetic counselling is a communication process that helps individuals, couples, and families understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease. It is provided by clinical geneticists and certified genetic counsellors.

Core principles: (1) Non-directiveness — the genetic counsellor provides accurate information, explores the patient's values and circumstances, and supports autonomous decision-making without steering toward any particular choice. This is especially important in reproductive decisions, predictive testing, and decisions about risk-reducing interventions. (2) Informed consent — before any predictive or diagnostic genetic test, the patient must understand: the nature and purpose of the test; possible outcomes (positive, negative, VUS); implications of each result for the patient and their relatives; potential for psychological harm; implications for insurance and employment; the option to decline testing. Pre-test and post-test counselling sessions are standard for predictive testing (e.g., Huntington disease testing). (3) Confidentiality and the duty to warn — genetic information belongs to the individual patient, but results have direct implications for biologically related family members. Ethical tension exists between the clinician's duty of confidentiality to the index patient and the potential duty to warn identifiable at-risk relatives. Current NZ guidance and legal frameworks support facilitating disclosure by the patient to relatives, but do not generally require clinicians to breach confidentiality — except in exceptional circumstances where there is serious imminent harm to an identifiable third party that cannot otherwise be prevented. (4) Predictive testing in minors — for late-onset, non-actionable conditions (e.g., Huntington disease, BRCA1/2 testing in an unaffected child), current consensus defers testing until the individual can provide autonomous informed consent as an adult. For childhood-onset, actionable conditions (e.g., FAP — prophylactic surveillance colonoscopy from early adulthood), testing in adolescence may be appropriate after careful counselling. (5) Psychological impact — receiving a genetic diagnosis (or a positive predictive test result) can cause significant psychological distress, survivor guilt, family conflict, and insurance/employment discrimination. Psychological support services and peer support groups should be offered.

BRCA1/2 — cascade testing in NZ: when a BRCA1/2 pathogenic variant is identified in a proband, cascade testing of first-degree relatives is recommended. In New Zealand, Māori and Pacific women carry population-specific (founder) BRCA1/2 variants that differ from those common in European populations (e.g., the BRCA2 c.5576_5579del variant found in some Māori families, and Polynesian-specific haplotypes). These variants may not be detected by targeted mutation testing panels designed for European populations — requiring comprehensive sequencing. Culturally appropriate genetic counselling that acknowledges whakapapa (genealogy) and the collective significance of genetic information for whānau is essential. Health equity: Pacific and Māori women with hereditary breast cancer risk must have equitable access to genetic testing, risk-reducing surgery, and surveillance — historically, rates of testing and cascade testing have been lower in these communities.

BRCA1/2 risk management options: surveillance (annual breast MRI from age 25-30, combined with mammography from age 30-40, depending on BRCA gene and protocol); risk-reducing bilateral salpingo-oophorectomy (RRBSO) — reduces ovarian cancer risk by >95%, also reduces breast cancer risk if performed before natural menopause (~50% reduction); risk-reducing bilateral mastectomy — reduces breast cancer risk by ~95%; chemoprevention (tamoxifen, raloxifene — evidence-based for BRCA1 is limited; more evidence in BRCA2 and non-hereditary high risk).

PRENATAL DIAGNOSIS

Chorionic villus sampling (CVS): biopsy of the placenta (chorionic villi) under ultrasound guidance, performed at 10-13 weeks gestation (transabdominal or transcervical route). Provides fetal cells for karyotype, microarray, or molecular testing. Advantages: early result (first trimester); if termination is chosen, first-trimester procedure is less traumatic. Limitations: placental mosaicism (confined placental mosaicism — abnormal cells in placenta but not fetus — may cause false positive result, requiring amniocentesis confirmation); miscarriage risk approximately 0.5-1% (procedure-related, above background; some studies suggest lower with experienced operators).

Amniocentesis: aspiration of amniotic fluid under ultrasound guidance at 15-18 weeks gestation. Amniotic fluid contains fetal cells (amniocytes) shed from fetal skin, amnion, and urinary tract. Lower miscarriage risk than CVS (~0.3-0.5% procedure-related). Advantage: lower mosaicism rate; can also measure alpha-fetoprotein (AFP) for neural tube defect screening; second-trimester-specific biochemical assays.

Non-invasive prenatal testing (NIPT / cfDNA screening): cell-free fetal DNA (cfDNA) derived from apoptotic trophoblastic cells constitutes approximately 10% (fetal fraction) of cell-free DNA in maternal plasma from 10 weeks gestation. NIPT analyses cfDNA for chromosomal imbalances. Sensitivity: >99% for trisomy 21; >97% for trisomies 18 and 13; lower for sex chromosome aneuploidies. Specificity: very high, but false positives occur. Positive predictive value (PPV): depends critically on background prevalence of the condition in the tested population — in a 25-year-old woman (low background risk), a positive NIPT for trisomy 21 has PPV ~60-90% (depending on specificity assumptions); in a 40-year-old, PPV approaches 99%. Therefore, all positive NIPT results require confirmation by invasive testing (CVS or amniocentesis) before any irreversible decision. NIPT does NOT replace CVS or amniocentesis — it is a screening test, not a diagnostic test. Limitations: cannot reliably detect all aneuploidies; false negatives possible (low fetal fraction, especially in obese patients); confined placental mosaicism may give discordant results.