Genetics: Mendelian Inheritance & Chromosomal Disorders

Genetics is the study of heredity — how traits are transmitted from parents to offspring. Mendelian principles, first described by Gregor Mendel in 1865 using pea plants, form the foundation of our understanding of single-gene (monogenic) inheritance. Chromosomal disorders arise from abnormalities in chromosome number or structure.

Mendelian Principles

Mendel's first law (Law of Segregation): Each organism carries two alleles for each gene; these segregate during gamete formation so each gamete receives one allele. Mendel's second law (Law of Independent Assortment): Alleles of different genes assort independently during gamete formation — valid when genes are on different chromosomes (or far apart on the same chromosome); linked genes violate this law.

Dominant and recessive: A dominant allele produces its phenotype in one copy (heterozygous or homozygous). A recessive allele produces its phenotype only in the homozygous state. In a standard Punnett square cross of two carriers (Aa × Aa): 25% AA, 50% Aa, 25% aa — phenotypic ratio 3:1 (dominant:recessive).

Patterns of Inheritance

Autosomal dominant (AD): One mutant allele sufficient. Affects males and females equally. Vertical transmission (every generation typically affected). 50% risk to offspring of affected individual. Examples: Huntington disease (HTT, trinucleotide repeat expansion), familial hypercholesterolaemia (LDLR mutation), Marfan syndrome (FBN1), neurofibromatosis type 1 (NF1), achondroplasia (FGFR3 gain-of-function). Penetrance (proportion of mutation carriers who express the phenotype) and expressivity (severity among those who express it) can vary.

Autosomal recessive (AR): Two mutant alleles required. Often parents are unaffected carriers (25% risk to offspring of two carriers). May appear to skip generations. Increased risk with consanguinity. Examples: cystic fibrosis (CFTR), sickle-cell disease (HBB p.Glu6Val), PKU (PAH), haemochromatosis (HFE C282Y), spinal muscular atrophy (SMN1 deletion), Gaucher disease (GBA).

X-linked recessive (XLR): Gene on the X chromosome; females are carriers (XX, one mutant allele, usually unaffected); males are affected (XY, one X chromosome, hemizygous). No male-to-male transmission. Carrier females have 50% chance of affected sons, 50% chance of carrier daughters. Examples: haemophilia A (F8) and B (F9), Duchenne muscular dystrophy (DMD), G6PD deficiency, Becker muscular dystrophy, red-green colour blindness.

X-linked dominant (XLD): Rare. Affects both sexes, but often more severely in males. Examples: fragile X syndrome (FMR1 CGG repeat expansion — note fragile X has complex inheritance with anticipation), incontinentia pigmenti (IKBKG), Rett syndrome (MECP2).

Mitochondrial: Transmitted exclusively maternally. All children of an affected mother may be affected; none of an affected father's children are affected. Variable expressivity due to heteroplasmy (mixture of normal and mutant mtDNA). Examples: MELAS (m.3243A>G), MERRF, Leber's hereditary optic neuropathy.

Co-dominance: Both alleles expressed equally (e.g., ABO blood groups, MN blood groups, HbAS sickle-cell trait).

Incomplete dominance: Heterozygote has an intermediate phenotype (e.g., familial hypercholesterolaemia heterozygotes have intermediate LDL levels).

Special Inheritance Phenomena

Anticipation: Increasing severity and earlier onset in successive generations due to expansion of trinucleotide repeats (dynamic mutations). Examples: Huntington disease (CAG, >36 repeats pathogenic), myotonic dystrophy type 1 (CTG, DMPK), fragile X (CGG, FMR1 — premutation 55–200 repeats, full mutation >200).

Genomic imprinting: Differential expression of alleles depending on parental origin, due to epigenetic marks (methylation). Prader-Willi syndrome (loss of paternal 15q11-q13, or maternal UPD15) and Angelman syndrome (loss of maternal 15q11-q13, or paternal UPD15) — same chromosomal region, different phenotype depending on which parental allele is lost.

Uniparental disomy (UPD): Inheritance of both copies of a chromosome from one parent. Can cause imprinting disorders or reveal recessive alleles (isodisomy).

Chromosomal Disorders

Normal human karyotype is 46,XX (female) or 46,XY (male) — 22 pairs of autosomes and 1 pair of sex chromosomes. Chromosomal abnormalities affect number (aneuploidy, polyploidy) or structure (deletions, duplications, inversions, translocations).

Trisomy 21 (Down syndrome): 47,+21; most common viable autosomal trisomy. Features: intellectual disability, characteristic facies (upslanting palpebral fissures, epicanthic folds, flat nasal bridge), single palmar crease, atlantoaxial instability, congenital heart defects (AVSD most characteristic, also VSD, ASD), duodenal atresia, hypothyroidism, increased risk of leukaemia (ALL, AML), and Alzheimer disease (APP overexpression on chr 21). ~95% from maternal non-disjunction.

Trisomy 18 (Edwards syndrome): 47,+18; severe intellectual disability, rocker-bottom feet, overlapping fingers, VSD, micrognathia; often fatal in infancy.

Trisomy 13 (Patau syndrome): 47,+13; holoprosencephaly, midline facial defects, polydactyly, severe intellectual disability; often fatal in infancy.

Turner syndrome (45,X): Short stature, primary amenorrhoea, streak gonads, infertility, webbed neck, bicuspid aortic valve, coarctation of the aorta. Normal intelligence. Treated with oestrogen replacement and growth hormone.

Klinefelter syndrome (47,XXY): Tall stature, small testes, infertility (azoospermia), gynaecomastia, learning difficulties (mild). Treated with testosterone replacement.

Chromosomal structural abnormalities: Deletions (e.g., del(22q11) — DiGeorge syndrome: cardiac defects, hypocalcaemia, immunodeficiency, cleft palate, learning difficulties — caused by haploinsufficiency of TBX1 and other genes); Translocations (e.g., Robertsonian translocation of chromosomes 14 and 21 — carrier has 45 chromosomes but is phenotypically normal, with 1/6 risk of offspring with Down syndrome); Inversions; Ring chromosomes.

Genetic Counselling Principles

Genetic counselling is a non-directive communication process providing information about the nature, inheritance, and implications of a genetic condition. Key components: accurate diagnosis, risk assessment, explanation of inheritance pattern, discussion of genetic testing options (prenatal: amniocentesis, CVS; preimplantation genetic diagnosis), psychosocial support, and discussion of reproductive options.