Inheritance and chromosomal disorders

Types of mutation

• A mutation is a permanent change in DNA. Germline mutations are in every cell and can be passed on; somatic mutations arise in one tissue (for example from a carcinogen such as tobacco or radiation) and are not inherited.

• Dominant-negative: a mutant subunit spoils the normal protein, as with a glycine substitution in collagen (severe osteogenesis imperfecta); a null allele gives milder disease.

Cancer syndromes: dominant inheritance, recessive at the cell

• Most inherited cancer syndromes are autosomal dominant at the family level, yet the gene is a tumour suppressor: one faulty copy is inherited in every cell, and a tumour starts when the second copy is lost (two-hit hypothesis).

Single-gene inheritance

• Penetrance: whether a carrier shows disease at all. Risk to a child = 1/2 × penetrance, so 80% penetrance gives 40%. Expressivity: how severe it is. Pleiotropy: one gene, many organs.
• Germline mosaicism: a "new" dominant mutation that recurs in siblings because a parent's gonads carry it.
• Haemochromatosis: commonest cause is homozygous HFE C282Y; low hepcidin causes excess iron absorption, giving diabetes, pigmentation, hepatomegaly and high transferrin saturation.
• Spinal muscular atrophy: autosomal recessive homozygous deletion of SMN1, losing anterior horn cells: profound hypotonia, absent reflexes, tongue fasciculation, paradoxical breathing, yet an alert infant with normal face and normal CK. Some carriers have two SMN1 copies on one chromosome and test "normal" on copy counting.
• Noonan syndrome: autosomal dominant (often PTPN11, RAS pathway) with a normal karyotype: webbed neck, short stature, pectus, pulmonary valve stenosis. It looks like Turner but affects both sexes.

Population genetics and consanguinity

• Hardy–Weinberg (autosomal): p + q = 1; affected = q², carriers = 2pq. If 1 in 10,000 is affected, q = 1/100 and carriers are about 1 in 50.
• X-linked: males have one X, so affected males = q; affected females = q². If 1 in 20 men is colour blind, about 1 in 400 women are.
• Consanguinity: first cousins share 1/8 of their genes by descent; their child is homozygous by descent at 1/16 of loci, roughly doubling the risk of recessive disease.

Chromosomal disorders: how they arise

• Meiotic non-disjunction causes about 95% of Down syndrome, mostly in maternal meiosis I. Oocytes stay arrested in prophase I from fetal life and cohesin weakens over decades, so risk rises with maternal age: about 1 in 1,500 at 20, 1 in 350 at 35, 1 in 100 at 40. Down syndrome is the commonest chromosomal cause of learning disability.
• Mitotic non-disjunction after fertilisation gives mosaicism (milder features).
• Robertsonian translocation: long arms of two acrocentric chromosomes fuse; the carrier is healthy with 45 chromosomes. About 4% of Down syndrome (46 chromosomes, often 14;21). A 21;21 carrier has 100% affected live births. Reciprocal translocation carriers have recurrent miscarriage.
• Triploidy (69 chromosomes) depends on parental origin. Two sperm and one egg (diandric, often 69,XXY) give a partial mole with fetal parts and scalloped villi. A diploid egg from a retained polar body plus one sperm (digynic) gives a small non-molar placenta, asymmetric growth restriction and very low hCG.
• Uniparental genomes: a complete mole is 46,XX with all-paternal DNA, usually from an empty ovum fertilised by one sperm that duplicates; a benign cystic teratoma is 46,XX with all-maternal DNA from an oocyte after meiosis I. Paternal alleles in a choriocarcinoma that are absent from the patient's blood prove gestational origin.
• Trisomy 16 is the commonest trisomy in first-trimester miscarriages and is never liveborn.
• Pseudoautosomal regions (PAR1, PAR2) at the tips of X and Y are homologous, allowing the X and Y to pair and cross over in male meiosis. SHOX lies in PAR1; SRY lies just outside it, so a faulty crossover can carry SRY to the X (46,XX male).

Autosomal trisomies

Sex chromosome disorders and disorders of sex development

• Turner (45,X): usually the paternal sex chromosome is lost, so it is not linked to maternal age. Short stature (one SHOX copy), webbed neck, cystic hygroma, streak ovaries with primary amenorrhoea and high FSH, coarctation and bicuspid aortic valve, horseshoe kidney. 45,X has no Barr body; a Barr body in a Turner phenotype suggests mosaicism or a structural X (isochromosome Xq).
• Klinefelter (47,XXY): tall, long legs, small firm testes, azoospermia, gynaecomastia; male breast cancer risk rises markedly.
• Barr bodies = number of X chromosomes minus one (XIST silencing).
• 46,XY gonadal dysgenesis (Swyer): female phenotype, uterus present (no AMH), streak gonads, no breast development; gonadoblastoma risk, so gonads are removed. The same applies to 45,X/46,XY mosaics.
• Androgen insensitivity (46,XY): breasts present, blind vagina, no uterus, inguinal testes.
• 46,XX with virilised genitalia but uterus and ovaries: congenital adrenal hyperplasia (21-hydroxylase deficiency).

Remember Pedigree shortcut: male-to-male transmission rules out X-linked inheritance.

Exam trap A Down syndrome child with 46 chromosomes means translocation: karyotype the parents, because recurrence risk is high.

Exam trap For X-linked traits the male frequency is q itself; apply q² only to females.

How FCPS asks about this

• Autosomal dominant cancer syndrome with a tumour suppressor gene: FAP (APC); Li–Fraumeni is germline TP53.
• Huntington parent: 50% of children affected, anticipation via CAG repeats.
• Carrier frequency when 1 in 10,000 is affected: about 1 in 50.
• Webbed neck and pulmonary stenosis in a boy with 46,XY: Noonan syndrome.
• Klinefelter man, increased cancer: breast carcinoma.
• Commonest cause of Down syndrome: maternal meiosis I non-disjunction; translocation if 46 chromosomes.
• Floppy infant, tongue fasciculations, consanguineous parents: homozygous SMN1 deletion.