Pathology chapters
Mendelian and other genetic disorders
The patterns of single-gene inheritance with their classic diseases, the common chromosomal disorders (Down, Edwards, Patau, Klinefelter and Turner syndromes), and the special patterns (trinucleotide repeats, mitochondrial inheritance and imprinting), with worked risk examples for cousin marriages.
- Autosomal dominant disorders show in every generation with a 50% risk to each child of an affected parent and usually involve structural proteins or receptors (Marfan, familial hypercholesterolaemia, adult polycystic kidney, Huntington); autosomal recessive disorders need two faulty copies, carrier parents have a 25% risk per child, and most are enzyme defects (thalassaemia, cystic fibrosis, sickle cell, PKU); X-linked recessive disorders affect males through carrier mothers (haemophilia, Duchenne, G6PD deficiency).
- Down syndrome (trisomy 21) is the commonest chromosomal disorder, mostly from maternal meiotic non-disjunction (risk rises with maternal age), with about 4% due to Robertsonian translocation.
- Klinefelter (47,XXY): tall, hypogonadal male with gynaecomastia and Barr body; Turner (45,X): short female with streak ovaries, webbed neck and coarctation of the aorta.
On this page
Overview
Genetic disorders fall into three main groups:
- Single-gene (Mendelian) disorders: a mutation in one gene with a clear inheritance pattern.
- Chromosomal disorders: changes in chromosome number or structure.
- Multifactorial (complex) disorders: many genes plus environment (diabetes, hypertension, cleft lip, neural tube defects).
Plus special patterns: trinucleotide repeat, mitochondrial and imprinting disorders.
Single-gene disorders
Autosomal dominant
- One faulty copy is enough; males and females equally affected.
- Vertical transmission: seen in every generation.
- An affected parent has a 50% chance of passing it to each child.
- Variable expressivity (severity differs) and incomplete penetrance (some carriers show nothing); onset often in adult life.
- Usually affect structural proteins or receptors.
Examples: Marfan syndrome (fibrillin-1), familial hypercholesterolaemia (LDL receptor), adult polycystic kidney disease, Huntington disease, neurofibromatosis types 1 and 2, achondroplasia, familial adenomatous polyposis, hereditary spherocytosis, von Willebrand disease (most types).
Autosomal recessive
- Two faulty copies needed; carriers are healthy.
- Horizontal pattern: affected siblings, parents unaffected.
- Consanguineous (cousin) marriage raises the risk, which matters in Pakistan, where cousin marriage is common.
- Onset often early in life; mostly enzyme defects.
Examples: β-thalassaemia, sickle cell disease, cystic fibrosis, phenylketonuria, lysosomal storage diseases (Tay-Sachs, Gaucher, Niemann-Pick), glycogen storage diseases, haemochromatosis, Wilson disease, albinism, congenital adrenal hyperplasia, most inborn errors of metabolism.
Father Aa × Mother Aa (A = normal, a = faulty)
Punnett square:
A a
A AA Aa
a Aa aa
AA = 1/4 = 25% normal, not a carrier
Aa = 2/4 = 50% carriers like the parents
aa = 1/4 = 25% affected
Each pregnancy carries the same 25% risk; it does not "use up" the risk.
Healthy sibling of an affected child: 2 of the 3 unaffected outcomes are Aa
→ chance of being a carrier = 2/3
X-linked recessive
- Males (one X) are affected; females are usually carriers.
- No male-to-male transmission (a father gives his son the Y).
- An affected father passes the gene to all daughters (carriers) and no sons.
- A carrier mother: 50% of sons affected, 50% of daughters carriers.
Examples: haemophilia A and B, Duchenne and Becker muscular dystrophy, G6PD deficiency, colour blindness, Lesch-Nyhan syndrome, Wiskott-Aldrich syndrome, X-linked agammaglobulinaemia (Bruton), Fabry disease.
Carrier mother (XᴴXʰ) × normal father (XᴴY)
Sons: XᴴY or XʰY → 1/2 normal, 1/2 affected
Daughters: XᴴXᴴ or XᴴXʰ → 1/2 normal, 1/2 carriers
Affected father (XʰY) × normal mother (XᴴXᴴ)
Sons: all XᴴY → none affected
Daughters: all XᴴXʰ → all carriers
X-linked dominant (rare): affected fathers pass it to all daughters; example: hypophosphataemic (vitamin D-resistant) rickets.
Chromosomal disorders
Karyotype analysis (usually from blood lymphocytes, amniotic cells or chorionic villi, arrested in metaphase) shows chromosome number and structure.
Mechanisms:
- Non-disjunction: chromosomes fail to separate at meiosis, giving trisomy or monosomy.
- Translocation: exchange of parts between chromosomes. Robertsonian translocation joins two acrocentric chromosomes (for example 14 and 21).
- Deletions (for example 22q11 deletion: DiGeorge syndrome; 5p deletion: cri du chat), mosaicism.
Autosomal trisomies
| Syndrome | Karyotype | Key features |
|---|---|---|
| Down syndrome | Trisomy 21 | The commonest chromosomal disorder in live births; intellectual disability, flat face, upslanting palpebral fissures, epicanthic folds, single palmar crease, sandal gap, congenital heart disease (AV septal defect), duodenal atresia, Hirschsprung disease, acute leukaemia, early Alzheimer disease, hypothyroidism |
| Edwards syndrome | Trisomy 18 | Rocker-bottom feet, clenched fists with overlapping fingers, small jaw, prominent occiput, heart defects; most die in infancy |
| Patau syndrome | Trisomy 13 | Cleft lip and palate, polydactyly, microcephaly, holoprosencephaly, eye defects (microphthalmia), heart defects; most die in infancy |
Causes of Down syndrome:
- Meiotic non-disjunction in the ovum (about 95%): risk rises with maternal age.
- Robertsonian translocation (about 4%): not related to maternal age; can be familial (a parent is a balanced carrier).
- Mosaicism (about 1%): milder features.
Down syndrome is mainly maternal non-disjunction, linked to maternal age. The translocation form is not age-related and can recur in families.
Sex chromosome disorders
| Feature | Klinefelter syndrome | Turner syndrome |
|---|---|---|
| Karyotype | 47,XXY | 45,X (also mosaics) |
| Sex | Male | Female |
| Barr body | Present (one) | Absent |
| Build | Tall, long legs, eunuchoid | Short stature |
| Gonads | Small, firm testes; azoospermia → infertility | Streak ovaries → primary amenorrhoea, infertility |
| Hormones | Low testosterone, high FSH and LH | Low oestrogen, high FSH and LH |
| Other | Gynaecomastia, sparse body hair, learning difficulties in some | Webbed neck, lymphoedema of hands and feet at birth (cystic hygroma), coarctation of the aorta, bicuspid aortic valve, horseshoe kidney, wide-spaced nipples |
Klinefelter is the commonest cause of male hypogonadism; Turner is the commonest cause of primary amenorrhoea due to gonadal failure.
Barr body: an inactivated X chromosome seen in the nucleus. Number of Barr bodies = number of X chromosomes minus one.
Disorders with non-classic inheritance
Trinucleotide repeat disorders
An expanded repeat of three nucleotides; the repeat tends to grow in each generation, so disease appears earlier and more severely (anticipation).
| Disorder | Repeat | Notes |
|---|---|---|
| Fragile X syndrome | CGG (FMR1 gene on X) | A common inherited cause of intellectual disability in boys; long face, large jaw, large testes (macro-orchidism), large ears |
| Huntington disease | CAG | Autosomal dominant; chorea, dementia; caudate nucleus atrophy |
| Myotonic dystrophy | CTG | Myotonia, cataracts, frontal baldness |
| Friedreich ataxia | GAA | Autosomal recessive; ataxia, cardiomyopathy |
Mitochondrial inheritance
Mitochondrial DNA comes only from the mother, so an affected mother passes the disorder to all her children; affected fathers pass it to none. Mostly affects tissues with high energy use (nerve, muscle). Example: Leber hereditary optic neuropathy, MELAS.
Genomic imprinting
Some genes are expressed from only one parent's copy. A deletion of 15q11–13:
- inherited from the father → Prader-Willi syndrome (obesity, hyperphagia, hypogonadism, intellectual disability);
- inherited from the mother → Angelman syndrome ("happy puppet": laughter, seizures, ataxia, severe intellectual disability).
Prenatal diagnosis and prevention
- Carrier screening and genetic counselling for families with thalassaemia and before cousin marriages.
- Prenatal diagnosis: chorionic villus sampling (about 10–13 weeks), amniocentesis (about 15–20 weeks), maternal screening (nuchal translucency, serum markers, cell-free DNA).
- Pakistan's thalassaemia programmes use premarital screening and counselling to cut the number of affected births.
Expect: features of AD, AR and X-linked inheritance with examples, risk calculations for carrier parents and X-linked carriers, no male-to-male transmission, Down syndrome features and causes (non-disjunction vs translocation, maternal age), Edwards and Patau features, Klinefelter vs Turner (karyotype, Barr bodies, features), anticipation and trinucleotide repeats, mitochondrial inheritance, and Prader-Willi vs Angelman.
Quick revision
- AD: vertical, 50%, structural proteins (Marfan, FH, ADPKD, Huntington).
- AR: siblings, 25% from two carriers, enzymes (thalassaemia, CF, PKU, storage diseases).
- X-linked recessive: males, carrier mothers; no male-to-male (haemophilia, Duchenne, G6PD).
- Down: trisomy 21, maternal non-disjunction, AV septal defect, duodenal atresia, leukaemia, Alzheimer.
- Edwards (18): clenched fists, rocker-bottom feet. Patau (13): cleft lip, polydactyly.
- Klinefelter 47,XXY (Barr body+); Turner 45,X (Barr body−, coarctation).
- Anticipation: trinucleotide repeats. Mitochondrial: mother to all children.
- 15q deletion: paternal = Prader-Willi; maternal = Angelman.
Written by The House Job from standard pathology references (Robbins and Cotran Pathologic Basis of Disease is the book named in the UHS PGET syllabus).
FAQ
If both parents carry an autosomal recessive gene, what is the risk for each child?
A 25% chance of being affected, 50% of being a carrier and 25% of being neither, in every pregnancy.
Why is there no male-to-male transmission in X-linked disorders?
A father passes his Y chromosome, not his X, to his sons.
What is the commonest cause of Down syndrome?
Non-disjunction of chromosome 21 during meiosis in the mother's egg, which becomes more likely with increasing maternal age.
What is the difference between Klinefelter and Turner syndrome?
Klinefelter syndrome is 47,XXY in a tall, infertile male with small testes; Turner syndrome is 45,X in a short female with streak ovaries, webbed neck and coarctation of the aorta.