Genetic disorders

Autosomal dominant

• One faulty copy is enough, often because the gene makes a structural protein or receptor. An affected parent passes it to 50% of children, both sexes, in a vertical pedigree.
• Features: variable expressivity, incomplete penetrance, new mutations (older fathers), late onset.
• Examples: adult polycystic kidney disease, familial hypercholesterolaemia, Marfan (fibrillin-1), neurofibromatosis, tuberous sclerosis, Huntington, achondroplasia (FGFR3), FAP, hereditary spherocytosis, osteogenesis imperfecta, von Willebrand disease (commonest inherited bleeding disorder), myotonic dystrophy, Ehlers–Danlos (most types), Noonan, Crouzon.
• Ehlers–Danlos syndrome: faulty collagen synthesis or processing gives hypermobile joints, hyperextensible skin and poor "cigarette-paper" scars.
• Noonan syndrome (RAS pathway, PTPN11): webbed neck, short stature, low hairline, pectus and pulmonary valve stenosis with a normal karyotype, in boys or girls. Turner syndrome looks similar but is 45,X with coarctation.
• Craniosynostosis with FGFR2 mutations: Crouzon (midface hypoplasia, proptosis, normal hands) and Apert (same face plus syndactyly).

Autosomal recessive

• Usually enzyme defects, where half the enzyme is enough. Two carrier parents give 25% affected, 50% carriers, 25% normal; affected siblings in one generation; consanguinity raises risk.
• Examples: cystic fibrosis, sickle cell disease, beta-thalassaemia, PKU, haemochromatosis (commonest AR disorder in Europeans), Wilson disease, alpha-1 antitrypsin deficiency, congenital adrenal hyperplasia, most storage diseases, xeroderma pigmentosum and most DNA repair syndromes.
• Cystic fibrosis: faulty CFTR chloride channel (chromosome 7, F508del). Less chloride is secreted, so less water follows and sodium absorption rises; mucus in lungs and pancreatic ducts becomes thick. Recurrent chest infections, bronchiectasis, steatorrhoea and fat-soluble vitamin deficiency (vitamin K, bleeding). Confirm with the sweat chloride test (sweat glands cannot reabsorb chloride).
• Hereditary haemochromatosis (HFE): low hepcidin lets the gut absorb too much iron; diabetes, bronze skin, arthropathy of 2nd and 3rd MCP joints, hepatomegaly, very high transferrin saturation and ferritin. First-line treatment is regular venesection.
• Why thalassaemia stays common in Pakistan: carriers resist falciparum malaria (heterozygote advantage), so selection keeps the allele frequent. Consanguinity explains why affected births are common.
• Locus heterogeneity: the same disease can come from different genes. Two deaf parents with recessive deafness in different genes have children who are all double heterozygotes with normal hearing.

Calculating carrier and recurrence risk

• Hardy–Weinberg: if disease frequency is q² = 1/10,000, then q = 1/100 and the carrier frequency 2pq is about 1/50.
• A healthy sibling of an affected person has a 2/3 chance of being a carrier, not 1/2, because the affected genotype is already excluded.
• So her child with an unrelated man from the same population has a risk of 2/3 × 1/50 × 1/4 = 1/300.

X-linked inheritance

• X-linked recessive: males affected; no male-to-male transmission; an affected father makes all daughters carriers; a carrier mother gives 50% of sons the disease. Examples: Duchenne and Becker, haemophilia A and B, G6PD deficiency, colour blindness, Lesch–Nyhan, Fabry, Hunter, Bruton agammaglobulinaemia, Wiskott–Aldrich, most chronic granulomatous disease, androgen insensitivity.
• Lyonisation: one X in each female cell is randomly inactivated early in embryonic life, forming the Barr body (seen on neutrophils as a drumstick appendage). If inactivation is skewed, a carrier may express the disease: a mother of a haemophiliac boy with factor VIII at 18% bleeds after dental extraction. Measure factor levels in carriers before surgery.
• Barr bodies = number of X chromosomes minus one: present in Klinefelter (XXY), absent in Turner (45,X). A "Turner" girl with a Barr body is a mosaic (45,X/46,XX).
• Pseudoautosomal regions at the tips of X and Y are homologous, so the X and Y can pair and cross over in male meiosis. SRY lies just outside PAR1.
• X-linked dominant: affected father gives it to all daughters, no sons; examples hypophosphataemic rickets, Rett syndrome, Alport syndrome (most).
• Lesch–Nyhan (HGPRT deficiency, purine salvage): gout, self-mutilation, dystonia. Allopurinol lowers urate only; it does not change the neurological disease.

Mitochondrial, repeat and imprinting disorders

• Mitochondrial: passed only by the mother (sperm mitochondria are destroyed); heteroplasmy varies severity. Leber hereditary optic neuropathy, MELAS, MERRF (ragged red fibres).

• Fragile X is the commonest inherited cause of intellectual disability: long face, large ears, macro-orchidism. A grandfather with a premutation has normal intelligence (later tremor and ataxia); he passes it to all daughters, whose premutation may cause early menopause. The premutation expands to a full mutation during maternal meiosis, so the grandson is severely affected. A premutated man cannot have affected sons because sons get his Y.
• Imprinting at 15q11–13: Prader–Willi = loss of the paternal copy (hypotonia, hyperphagia, obesity, hypogonadism); Angelman = loss of the maternal UBE3A (happy, laughing, seizures, ataxia).

Multifactorial inheritance

• Many genes plus environment produce a liability; disease appears above a threshold. Recurrence risk is about 2–5% in first-degree relatives and rises with each affected relative and with severity, so after two affected babies with neural tube defects the risk is higher than after one. Never quote 25% or 50%.
• Carter effect: when one sex is less often affected (pyloric stenosis is five times commoner in boys), an affected woman must carry more liability, so her children, especially sons, have higher risk than the children of an affected man. This is the polygenic threshold model.
• Examples: cleft lip and palate, neural tube defects, congenital heart disease, pyloric stenosis, developmental dysplasia of the hip, type 2 diabetes. Multifactorial is the commonest pattern of genetic disease overall.

Chromosomal disorders

• Turner gonadotrophins: ovarian follicles undergo accelerated atresia, leaving streak ovaries. With no oestrogen or inhibin feedback, FSH and LH rise markedly. Mosaic girls may start puberty and fail later.
• Chromosomal microarray is now the first-line test for copy number variants (small deletions and duplications) in developmental delay; karyotype is used for trisomies and balanced rearrangements; FISH for a known deletion.
• Prenatal: combined test at 11–14 weeks (Down: raised nuchal translucency, low PAPP-A, high hCG); cell-free DNA screening; diagnosis by chorionic villus sampling or amniocentesis.

Inherited cancer syndromes

• Cancers keep dividing because they reactivate telomerase, which rebuilds the chromosome ends that normally shorten with each division.

Remember Dominant disorders break structures; recessive disorders break enzymes; X-linked disorders spare no son of a carrier half the time.

Exam trap A healthy sibling of someone with an AR disease is a carrier with probability 2/3, not 1/2.

Exam trap Klinefelter men have a Barr body; Turner women do not.

How FCPS asks about this

• Carrier risk sum (sibling affected, disease 1 in 10,000): 2/3 × 1/50 × 1/4 = 1 in 300.
• Female carrier of haemophilia who bleeds: skewed X-inactivation; drumstick appendages are the inactive X.
• Fragile X boy, normal mother and grandfather: premutation expanded during maternal meiosis.
• Pyloric stenosis risk higher in sons of affected women: polygenic threshold (Carter effect); recurrence after two NTDs is higher than after one.
• Webbed neck, pulmonary stenosis, normal 46,XY: Noonan syndrome; Turner raised FSH is from loss of ovarian follicles.
• Breast cancer with relatives' sarcoma and adrenal carcinoma: TP53; endometrial cancer with MSI is mismatch repair (Lynch).
• Cystic fibrosis: faulty CFTR reduces chloride and water secretion; confirm with sweat chloride test.