Introduction To Clinical Genetics
Clinical genetics is the medical specialty concerned with the diagnosis, counseling, and management of inherited or congenital disorders, many of which present in infancy, childhood, or adolescence when developmental and growth abnormalities first become apparent.
Introduction to Clinical Genetics (Paediatric Focus)
Clinical genetics is the medical specialty concerned with the diagnosis, management, counselling, and prevention of genetic diseases in individuals and families. In paediatrics, it is especially central because:
- ~5% of all live births have a genetic basis for disease, with ~2% having a significant congenital anomaly [1]
- Genetic diseases are collectively a leading cause of childhood morbidity, mortality, and intellectual disability
- Early genetic diagnosis enables targeted therapy (precision medicine), prognostication, reproductive counselling, and family support
- The clinical geneticist bridges the gap between molecular science and bedside care — a role every paediatrician must understand
What a safe clinician must not miss:
- Dysmorphic features in a newborn suggesting a chromosomal or syndromic diagnosis
- Family history patterns suggesting heritable risk (cancer predisposition, cardiomyopathy, haemoglobinopathy)
- The need for genetic counselling before and after genetic testing (informed consent, implications for family)
- Treatable genetic conditions (e.g. inborn errors of metabolism, Wilson disease) where delay causes irreversible harm
The following learning outcomes are adapted from the GC lecture slides and the National Genetics Education & Development Centre (NHS, UK): [2]
- Understand the basis of genetic disease — chromosomal, single gene (Mendelian), non-traditional mechanisms (imprinting, trinucleotide repeats, mitochondrial), multifactorial/polygenic
- Recognise inheritance patterns from a pedigree — AD, AR, XLR, XLD, mitochondrial, and non-Mendelian
- Understand key genetic concepts — penetrance vs. expressivity, de novo mutations, genetic anticipation, mosaicism, genetic heterogeneity (locus and allelic)
- Know the clinical approach to a dysmorphic/malformed child — systematic examination, syndrome recognition, when to refer
- Know the indications, strengths and limitations of genetic investigations — karyotype, FISH, aCGH (chromosomal microarray), NGS (gene panel, WES, WGS)
- Understand the role of genetic services — diagnostic certainty, management, prognosis, targeted therapy, reproductive counselling, family support
- Apply genetics to common paediatric conditions — thalassaemia, Down syndrome, Turner syndrome, Marfan syndrome, Fragile X, DMD, cancer predisposition syndromes
- Know how to counsel families — pre-marital, pre-pregnancy, prenatal, and post-diagnostic counselling
- Understand pharmacogenomics — how genetic variation affects drug response, toxicity, and dosing
- Know how to obtain current information about scientific and clinical applications of genetics, particularly from specialised genetics services [2]
| Category | Mechanism | Examples (Paediatric) |
|---|---|---|
| Chromosomal disorder | Aneuploidy, structural rearrangement | Trisomy 21 (Down), Trisomy 18 (Edwards), Trisomy 13 (Patau), Turner (45,X), Klinefelter (47,XXY) |
| Single gene (Mendelian) | AD, AR, XLR, XLD | Marfan (AD), CF (AR), DMD (XLR), Fragile X (XLD) |
| Non-traditional mechanisms | Trinucleotide repeats, imprinting, mitochondrial, uniparental disomy | Fragile X, Prader-Willi/Angelman, MELAS |
| Multifactorial / Polygenic | Gene-environment interaction | Neural tube defects, congenital heart disease, cleft lip/palate, Type 1 DM |
Individually rare but collectively numerous and important (> 6000 Mendelian disorders identified) [1]
Inheritance Patterns — Detailed Breakdown
| Pattern | Key Features | Pedigree Clue | Classic Paediatric Examples |
|---|---|---|---|
| Autosomal Dominant (AD) | 50% risk each child; affected in every generation; most common mode of inheritance [1]; male = female | Vertical transmission | Marfan syndrome, Familial hypercholesterolaemia, Achondroplasia, Noonan syndrome, NF1 |
| Autosomal Recessive (AR) | 25% risk if both parents carriers; often consanguinity; may skip generations | Horizontal pattern, unaffected parents | Cystic fibrosis, Thalassaemia, Sickle cell disease, PKU, Wilson disease |
| X-linked Recessive (XLR) | Males affected; females are carriers (may be mildly affected due to skewed X-inactivation); no male-to-male transmission | Males affected, carrier mothers | DMD/BMD, Haemophilia A/B, G6PD deficiency |
| X-linked Dominant (XLD) | Males and females affected; affected males may be more severe or lethal in utero | More affected females than males | Rett syndrome, Incontinentia pigmenti, Fragile X (partial) |
Key Concepts: Penetrance vs Expressivity
Penetrance = the percentage of individuals with a given genotype who exhibit any phenotypic manifestation at all (binary: yes/no). Expressivity = the degree/spectrum of phenotype expressed among those who do manifest the condition (continuous: mild → severe). [1][3]
Example: Marfan syndrome has high penetrance but variable expression — almost all carriers show some features, but severity varies widely even within the same family. [3]
| Mechanism | Key Concept | Examples |
|---|---|---|
| Trinucleotide repeat expansion | Increasing severity with increased expansion; increasing severity and earlier age of onset in subsequent generations (genetic anticipation) [4] | Fragile X (CGG), Huntington (CAG), Myotonic dystrophy (CTG), Friedreich ataxia (GAA), Spinocerebellar ataxia (CAG) |
| Genomic imprinting | Expression depends on parent-of-origin; same deletion → different disease depending on maternal vs paternal origin | Prader-Willi (paternal 15q11 deletion), Angelman (maternal 15q11 deletion) |
| Uniparental disomy | Both copies of a chromosome from one parent | Prader-Willi (maternal UPD 15) |
| Mitochondrial inheritance | Maternal inheritance only; heteroplasmy → variable expression | MELAS, MERRF, Leber hereditary optic neuropathy, MIDD |
| Mosaicism | Post-zygotic mutation → two cell populations | Trisomy 13 mosaicism (NOT associated with advanced maternal age), Somatic NF1 segmental mosaicism |
Trisomy 13 Mosaicism vs Full Trisomy
Trisomy 13 mosaicism is caused by a mitotic non-disjunction error (after fertilization) and is NOT associated with advanced maternal age, unlike full trisomy 13 which results from meiotic error and IS associated with advanced maternal age. [5] Students commonly confuse these.
Approach to the Malformed / Dysmorphic Child
This section aligns with GC 151: "A Child with congenital malformation – Introduction to Clinical Genetics" [2]
| Term | Definition | Example |
|---|---|---|
| Malformation | Intrinsic abnormality of morphogenesis (genetic/early embryonic) | Congenital heart defect, cleft palate |
| Deformation | Abnormal form/position due to extrinsic mechanical forces on otherwise normal tissue | Plagiocephaly from oligohydramnios |
| Disruption | Breakdown of previously normal tissue (vascular, amniotic bands) | Limb amputation from amniotic bands |
| Dysplasia | Abnormal cellular organization of tissue | Skeletal dysplasia, ectodermal dysplasia |
| Syndrome | Pattern of multiple anomalies with a single known or presumed cause | Down syndrome, Marfan syndrome |
| Sequence | Pattern of anomalies arising from a single initiating event | Potter sequence (renal agenesis → oligohydramnios → lung hypoplasia → limb deformities) |
| Association | Non-random co-occurrence of anomalies without a known unifying cause | VACTERL association |
- Detailed pregnancy and birth history — teratogen exposure, infections, gestational diabetes, prenatal screening results
- Comprehensive family history / pedigree — at least 3 generations, consanguinity, ethnicity, recurrent miscarriages, infant deaths
- Growth parameters — weight, length, head circumference plotted on age-appropriate charts
- Systematic dysmorphology examination — head to toe:
- Head: shape, fontanelles, hair pattern (abnormal whorls suggest abnormal brain growth)
- Face: facial gestalt, interpupillary distance (hyper/hypotelorism), ears (position, morphology), nose, philtrum, lips, palate
- Eyes: palpebral fissures, epicanthal folds, coloboma, Brushfield spots
- Hands/Feet: digits (poly/syndactyly, clinodactyly), palmar creases, nail hypoplasia, sandal gap
- Skin: pigmentation (café-au-lait spots, ash-leaf macules), haemangiomata, cutis laxa
- Genitalia: ambiguous genitalia, cryptorchidism, hypospadias
- Neurological: tone, reflexes, developmental milestones
- Investigations — guided by clinical suspicion (see below)
- Recognition of pattern — is this a known syndrome? Use databases (OMIM, GeneReviews, London Dysmorphology Database)
- Referral to clinical genetics service when pattern is unclear or when a genetic diagnosis would change management/counselling
The following hierarchy of genetic investigations is high-yield for exams and is drawn directly from the GC lecture slides and Adrian Lui Paediatrics Notes: [1][2][6]
| Investigation | Mechanism | Resolution | Detects | Limitations | Paediatric Indications |
|---|---|---|---|---|---|
| Karyotype (染色體核型分析) | Giemsa staining of metaphase chromosomes | ~5-10 Mb | Aneuploidy, large structural rearrangements (translocations, inversions, large deletions/duplications) | Low resolution; cannot detect submicroscopic changes | Suspected aneuploidy (Down, Turner, Klinefelter), ambiguous genitalia, recurrent miscarriages in parents |
| FISH (Fluorescence in situ hybridization) | Fluorescent DNA probes hybridize to specific chromosomal loci | Targeted (100 kb–1 Mb) | Presence/absence/number of specific sequences; useful for microdeletion syndromes [1] | Only tests for what you probe; cannot detect genome-wide changes | 22q11 deletion (DiGeorge), Williams (7q11), Prader-Willi/Angelman (15q11), subtelomeric rearrangements |
| aCGH (Array Comparative Genomic Hybridization) / Chromosomal Microarray (CMA) | Thousands of probes across genome | ~50-100 kb | Copy number variants (CNVs) — deletions and duplications genome-wide | Only quantitative — cannot detect balanced structural rearrangements (e.g. balanced translocation) [1]; cannot detect point mutations | First-tier test for unexplained GDD/ID, ASD, multiple congenital anomalies (replaces karyotype in many settings) |
| NGS — Gene Panel | Sequencing specific set of genes | Single nucleotide | Variants in specific set of genes known to be related to specific disease presentation [1] | Limited to genes on panel; may miss novel genes | Epilepsy panel, cardiomyopathy panel, skeletal dysplasia panel, RASopathy panel |
| WES (Whole Exome Sequencing) | Sequencing all coding regions (~1-2% of genome) | Single nucleotide | Point mutations, small indels in coding regions | Misses non-coding, structural, repeat expansions, epigenetic changes | Undiagnosed GDD/ID after CMA, suspected Mendelian disorder with no clear candidate |
| WGS (Whole Genome Sequencing) | Sequencing entire genome | Single nucleotide + structural | Everything WES detects + non-coding, structural variants, repeat expansions | Cost, data interpretation, incidental findings | Complex undiagnosed cases, research |
Types of WES/WGS: Singleton (proband only), Duo (proband + one parent), Trio (proband + both parents), Quad (proband + parents + sibling) [1]
Trio analysis is the gold standard for de novo variant detection — comparing child's genome to both parents allows rapid identification of new mutations.
CMA vs Karyotype — Exam Pitfall
CMA (aCGH) has largely replaced karyotype as the first-tier genetic investigation for children with unexplained intellectual disability or multiple congenital anomalies. However, karyotype is still needed when you suspect a balanced translocation (e.g. parent with recurrent miscarriages) because CMA cannot detect balanced rearrangements. Know both indications.
The role of clinical genetics includes: [1]
| Role | Explanation |
|---|---|
| Diagnostic certainty | Establishing a precise genetic diagnosis guides everything else |
| Management and follow-up | Many genetic syndromes have established surveillance protocols (e.g. annual echo in Marfan, cardiac screening in Williams) |
| Natural history and prognosis | Informing families what to expect — this reduces anxiety and enables planning |
| Targeted therapy | Enzyme replacement (Gaucher, Fabry, Pompe), substrate reduction, gene therapy, pharmacogenomics |
| Reproductive risk and family planning | Recurrence risk counselling, prenatal diagnosis options (CVS, amniocentesis, PGT, NIPT) |
| Patient and family support group | Connecting families with disease-specific support networks |
High-Yield Paediatric Genetic Conditions
Chromosomal Disorders
- Most common chromosomal cause of intellectual disability
- 95% due to meiotic non-disjunction (associated with advanced maternal age); 4% Robertsonian translocation (14;21 most common — important for recurrence risk); 1% mosaicism
- Features: hypotonia, flat facial profile, upslanting palpebral fissures, Brushfield spots, single palmar crease, sandal gap, CHD (AVSD most characteristic), duodenal atresia, Hirschsprung disease, hypothyroidism, ALL risk, Alzheimer's risk
- Screening: combined first-trimester screening (NT + PAPP-A + free β-hCG), NIPT, definitive diagnosis by karyotype/CMA
- Cleft lip/palate, polydactyly, microphthalmia, holoprosencephaly, CHD (80% — ASD, VSD, PDA, TGA)
- Median survival ~7-10 days; 90% mortality in first year
- Three genetic mechanisms: full trisomy 13 (meiotic error, ↑ with maternal age), mosaicism (mitotic error, NOT ↑ with maternal age), unbalanced Robertsonian translocation (NOT ↑ with maternal age)
- Clenched fists with overlapping fingers, rocker-bottom feet, CHD, micrognathia, prominent occiput
- Severe: median survival ~5-15 days
- Short stature (95%), delayed puberty, premature ovarian insufficiency (gonadal dysgenesis), webbed neck, shield chest, widely spaced nipples, cubitus valgus, coarctation of aorta
- Workup: karyotype for 45,XO
- Management: GH replacement, sex hormone replacement at pubertal age
Single Gene Disorders
- Mutation in fibrillin-1 (FBN1) gene on chromosome 15q21.1 (90%); TGFBR1/2 mutations in ~10%
- Almost exclusively AD; 25% are sporadic (de novo)
- High penetrance but variable expression
- Cardinal features: tall stature/arachnodactyly, lens subluxation (upward), aortic root dilatation/dissection, mitral valve prolapse, dural ectasia, pectus deformity, scoliosis
- Surveillance: regular echocardiography, ophthalmology
- Management: beta-blockers / ARBs to slow aortic root dilatation; activity restriction; surgical intervention for significant aortic dilatation
- CGG trinucleotide repeat expansion at 5' UTR of FMR1 gene (Xq27.3)
- Full mutation ( > 200 repeats): methylation → silencing of FMR1 → absent FMRP → classic phenotype
- Premutation (50-200 repeats): FMR1 remains transcriptionally active; associated with FXTAS (tremor/ataxia in older males), premature ovarian insufficiency in females
- Clinical: intellectual disability (more severe in males), long face, large ears, macro-orchidism (post-pubertal), joint hypermobility, behavioural issues (ADHD, anxiety, ASD features)
- Genetic anticipation applies: increasing severity with successive generations
- DMD gene (Xp21) mutations (30-60% deletions) → truncated/absent dystrophin → unstable muscle fibres → progressive degeneration
- Incidence: 1/3500 male births
- Onset ~5 years; progressive weakness (proximal → distal); loss of ambulation by 2nd decade; respiratory failure and death in 2nd-3rd decade
- Gower's sign (climbing up oneself); pseudohypertrophy of calves; cardiomyopathy; mild cognitive impairment
- Elevated CK (massively, 50-100x normal)
- Diagnosis: genetic testing (multiplex PCR/MLPA for deletions/duplications → sequencing if negative)
- Management: corticosteroids (deflazacort/prednisolone — proven to prolong ambulation), cardiac surveillance, respiratory support, physiotherapy, newer therapies (eteplirsen, ataluren for specific mutations)
- Becker MD: same gene, partial dystrophin expression → later onset, milder course, ambulatory beyond 15 years
- Most common single gene defect in Hong Kong (α-carrier: 5%; β-carrier: 3.5%) [10]
- α-thalassaemia: AR, gene deletions on Chr 16 (most common: SEA deletion)
- 1-2 deletions: trait; 3 deletions: HbH disease; 4 deletions: Hb Bart's → hydrops fetalis (non-viable)
- β-thalassaemia: AR, point mutations on Chr 11
- Major (β0/β0): severe, transfusion-dependent, presents 3-6 months (gamma-beta switch)
- Intermedia: variable severity
- Minor/Trait: mild microcytic anaemia, asymptomatic
- Molecular study of globin diseases is needed for: (1) atypical phenotypes, (2) confirming Hb variant identity, (3) prenatal diagnosis [11]
- CAG trinucleotide repeat expansion in Huntingtin (4p16.3)
- Genetic anticipation (especially paternal transmission)
- Onset typically ~40 years; chorea, psychiatric features, dementia; progressive and fatal in 10-15 years
- Paediatric relevance: juvenile Huntington (Westphal variant — akinetic/rigid rather than choreic; very large repeat numbers; paternal inheritance)
| Feature | Suggests Hereditary Cancer Predisposition |
|---|---|
| Young age at diagnosis | e.g. breast cancer < 40, colon cancer < 50 |
| Multiple cancers in same individual | |
| Bilateral tumours in paired organs | Bilateral retinoblastoma, bilateral breast CA |
| Multiple affected family members (≥ 2-3) across generations | Vertical pattern (AD) |
| Rare tumour types | Pheochromocytoma, medullary thyroid CA, retinoblastoma |
| Associated features | Multiple polyps (FAP), café-au-lait spots (NF1), hamartomas (PTEN) |
Pharmacogenomics is the study of how genetic variation affects an individual's response to drug therapy. The overarching clinical goal: to enable prescription of the right drug to the right patient to maximize efficacy and minimize toxicity. [13][14]
| Pharmacogene | Drug | Clinical Implication | Population Relevance |
|---|---|---|---|
| CYP2C19 | Clopidogrel | Poor metabolizers → reduced active metabolite → inadequate antiplatelet effect → use prasugrel/ticagrelor instead | ~15-20% East Asians are poor metabolizers |
| HLA-B*5801 | Allopurinol | 8% carrier frequency in Han Chinese → dramatically ↑ risk of SJS/TEN → must screen before prescribing [15] | Cost-effective screening in HK |
| VKORC1, CYP2C9 | Warfarin | Influence sensitivity and metabolism → pharmacogenomic-guided dosing reduces time to stable INR | |
| HLA-B*1502 | Carbamazepine | ↑ risk of SJS/TEN in Southeast Asians → must screen before prescribing | ~8% Han Chinese carriers |
| TPMT | Azathioprine / 6-MP | Poor metabolizers → severe myelosuppression | Important in paediatric ALL treatment |
| DPYD | 5-Fluorouracil | Deficiency → severe toxicity |
Pharmacogenes typically relate to pharmacokinetics (absorption, distribution, metabolism, excretion) or pharmacodynamics (response at drug target level) [13]
Content aligned with GC 238 and Block C Rare Disease Genetic Testing [6][16]
- Definition: A disease is considered "rare" when it affects < 1 in 2000 individuals (European definition) or < 1 in 1500 (US/Hong Kong)
- Collectively: > 7000 rare diseases affect ~6-8% of the population; ~80% have a genetic basis
- Diagnostic odyssey: average time to diagnosis 5-7 years; multiple specialists; significant family burden
- Clinical approach:
- Detailed phenotyping (HPO terms)
- Pedigree analysis
- Tiered genetic testing (CMA → gene panel → WES/WGS)
- Multidisciplinary team (MDT) discussion
- Functional validation if variant of uncertain significance (VUS) found
- Precision medicine: genetic diagnosis enables targeted therapy (e.g. enzyme replacement therapy, gene therapy, antisense oligonucleotides, substrate reduction therapy)
Genetic Counselling — Key Principles
- Before and after genetic testing (pre-test and post-test counselling)
- Family planning — pre-marital, pre-pregnancy, prenatal (CVS at 11-14 weeks, amniocentesis at 15-18 weeks, NIPT from 10 weeks)
- After diagnosis of a genetic condition in a child
- When family history suggests hereditary risk
- Non-directive: provide information, support autonomous decision-making
- Risk assessment: calculate recurrence risk based on inheritance pattern
- Explanation: diagnosis, natural history, prognosis in age-appropriate language
- Options: prenatal diagnosis, preimplantation genetic testing (PGT), carrier testing for relatives
- Psychosocial support: emotional impact, family dynamics, support groups
- Consent: genetic testing in children requires parental consent; consider the child's right to an open future (especially for adult-onset conditions like Huntington disease — generally defer predictive testing until the child can consent as an adult)
- Confidentiality and duty to warn: balancing patient confidentiality with potential harm to at-risk relatives
Ethics of Predictive Genetic Testing in Children
For adult-onset conditions (e.g. Huntington disease, BRCA), predictive testing in minors is generally deferred until the child reaches an age where they can give autonomous informed consent. Testing may be justified if there is a medical intervention in childhood that would alter management (e.g. FAP → colonoscopy from age 10-12; MEN2 → prophylactic thyroidectomy). Always discuss in MDT with genetics team.
| Screen | Timing | Purpose |
|---|---|---|
| Combined first-trimester screening | 11-13+6 weeks | Down syndrome risk (NT + PAPP-A + free β-hCG) |
| NIPT (Non-invasive prenatal testing) | ≥ 10 weeks | Cell-free fetal DNA in maternal blood; screening for T21, T18, T13, sex chromosome aneuploidies |
| Anomaly scan | 18-22 weeks | Structural abnormalities |
| Newborn screening (NBS) | Day 3-5 of life | In HK: congenital hypothyroidism, G6PD deficiency; expanded NBS programmes (IEM) being piloted |
| Haemoglobinopathy screening | Premarital/prenatal | Especially important in HK given high carrier rates of α- and β-thalassaemia |
Exam Approach
- "Draw a pedigree for this family and identify the inheritance pattern" → practise AD, AR, XLR pedigrees
- "A newborn has multiple congenital anomalies — describe your approach" → systematic dysmorphology + tiered genetic testing
- "What is the difference between penetrance and expressivity?" → classic definition question
- "What genetic test would you order for a child with unexplained GDD?" → CMA as first-tier, then WES
- "A couple are both β-thalassaemia carriers — what is the risk to their offspring and what prenatal options are available?" → 25% risk of β-thal major; CVS/amniocentesis for molecular diagnosis; NIPT; PGT-M
- "What pharmacogenomic test should be done before prescribing carbamazepine in a Chinese patient?" → HLA-B*1502
- Confusing penetrance with expressivity
- Forgetting that CMA cannot detect balanced translocations
- Stating that all trisomies are associated with advanced maternal age (mosaicism and Robertsonian translocations are NOT)
- Forgetting that β-thalassaemia presents at 3-6 months (after γ→β globin switch), not at birth
- Testing children for adult-onset conditions without ethical justification
High Yield Summary
- 5% of live births have genetic disease; 2% have significant congenital anomalies
- Classification: Chromosomal, Mendelian (AD/AR/XLR/XLD), non-traditional (trinucleotide repeats, imprinting, mitochondrial), multifactorial
- Penetrance = proportion who manifest disease at all; Expressivity = spectrum of severity among those affected
- Genetic anticipation = earlier onset and greater severity in successive generations (trinucleotide repeat disorders)
- First-tier test for unexplained GDD/MCA: CMA (aCGH); Karyotype still needed for suspected balanced rearrangements
- FISH for microdeletion syndromes (22q11, Williams, PWS/AS)
- WES/WGS (trio preferred) for undiagnosed cases after CMA
- Thalassaemia is the most common single gene defect in HK — carrier screening is essential
- Pharmacogenomics: HLA-B5801 before allopurinol, HLA-B1502 before carbamazepine in Chinese populations
- Genetic counselling is non-directive; predictive testing in children for adult-onset conditions should generally be deferred
Active Recall - Introduction to Clinical Genetics
[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (Ch 15 Clinical Genetics, pp.495-501) [2] Lecture slides: GC 151. The malformed child hereditary syndromes and anomalies.pdf (pp.1, 59, 60) [3] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Marfan syndrome, p.868) [4] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Fragile X syndrome, p.881) [5] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Trisomy 13, p.836) [6] Lecture slides: GC 238. Rare Disease Genetic Testing for Precision Medicine.pdf (p.3) [7] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Turner syndrome / Short stature, p.661) [8] Senior notes: Ryan Ho Neurology.pdf (Muscular Dystrophies, p.192) [9] Senior notes: Ryan Ho Haemtology.pdf (Beta thalassaemia, p.22) [10] Senior notes: Maksim Medicine Notes.pdf (Thalassemia, p.155) [11] Senior notes: Block A - Many members of the family have anaemia.pdf (Molecular study of globin diseases, p.34) [12] Senior notes: Ryan Ho Neurology.pdf (Huntington's Disease, p.127) [13] Lecture slides: Clinical Pharmacology- Introduction to Clinical pharmacology (I) (Pharmaco-Genomics, Precision Medicine).pdf (p.52) [14] Senior notes: Introduction to Clinical pharmacology (I) (Pharmaco- Genomics, Precision Medicine).pdf (p.1) [15] Senior notes: Learning_Points_All_Lectures.txt (Pharmacogenomics learning points) [16] Senior notes: Block C - Rare Disease Genetic Testing.pdf (p.1)
X-linked Agammaglobulinaemia
X-linked agammaglobulinaemia (Bruton disease) is a primary immunodeficiency caused by mutations in the BTK gene, resulting in failure of B-cell maturation and absence of immunoglobulins, typically presenting in boys after 6 months of age with recurrent sinopulmonary and other bacterial infections once maternal antibody wanes.
Fragile X Syndrome
Fragile X syndrome is an X-linked trinucleotide repeat expansion disorder in the FMR1 gene, representing the most common inherited cause of intellectual disability and autism spectrum features in children, particularly boys, typically presenting in early childhood with developmental delay, characteristic facial features, and behavioral difficulties.