2.4 Trinucleotide Repeat Disorders & Chromosomal Abnormalities

Dynamic Trinucleotide Repeat Expansions & Anticipation

Trinucleotide repeat disorders are caused by unstable tandem repeat expansions. During meiosis or mitotic replication, the repetitive tract slips, leading to hairpin loop formation during Okazaki fragment synthesis on the lagging strand, expanding the repeat length.

• Genetic Anticipation: Disease manifests at an increasingly younger age and with progressively greater clinical severity in subsequent generations as the repeat length expands.
• Parental Transmission Bias: Huntington disease expands most dramatically during paternal spermatogenesis, whereas Myotonic Dystrophy and Fragile X syndrome expand most extensively during maternal oogenesis.

[!TIP] High-Yield Distinction: Friedreich Ataxia vs Other Repeat Disorders: Friedreich ataxia is the only common trinucleotide repeat disorder inherited in an autosomal recessive fashion. Because both alleles must harbor pathogenic mutations, it does not demonstrate the intergenerational anticipation seen in dominant pedigrees. Intronic GAA expansion impairs transcription of frataxin, a mitochondrial iron-chaperone protein. Mitochondrial iron overload generates reactive oxygen species, destroying the posterior columns, corticospinal tracts, and spinocerebellar tracts, accompanied by hypertrophic cardiomyopathy (the leading cause of premature death).

Constitutional Chromosomal Aneuploidies & Translocations

Aneuploidy refers to an abnormal chromosome number that is not an exact multiple of the haploid number (23). It stems predominantly from meiotic nondisjunction, where homologous chromosomes (Meiosis I) or sister chromatids (Meiosis II) fail to separate. The incidence of meiotic nondisjunction correlates directly with advanced maternal age.

                       Meiotic Nondisjunction Outcomes
  Meiosis I Failure ──> All gametes abnormal (50% Disomic [Trisomy after fertilisation], 50% Nullisomic)
  Meiosis II Failure ──> 50% normal gametes, 25% Disomic (Trisomy), 25% Nullisomic (Monosomy)

Autosomal Trisomies

1. Down Syndrome (Trisomy 21; 47,XX/XY,+21):
   • Etiology: 95% meiotic nondisjunction (predominantly maternal Meiosis I); 4% unbalanced Robertsonian translocation (e.g., der(14;21)); 1% post-zygotic mitotic mosaicism.
   • Craniofacial and Physical Features: Brachycephaly, flat occiput, epicanthic folds, upslanting palpebral fissures, Brushfield spots (white speckles on the iris perimeter), single transverse palmar crease (simian crease), sandal gap between 1st and 2nd toes.
   • Structural Anomalies: Complete atrioventricular septal defect (AVSD / endocardial cushion defect, 40%), ventricular septal defect (VSD); gastrointestinal malformations including duodenal atresia ("double-bubble" sign on abdominal radiograph) and Hirschsprung disease.
   • Medical Complications: Early-onset Alzheimer's disease developing by age 40 (caused by triplication of the APP amyloid precursor protein gene on chromosome 21); acute lymphoblastic leukaemia (ALL, 20-fold increased risk) and acute megakaryoblastic leukaemia (AML-M7); coeliac disease, atlantoaxial instability, and hypothyroidism.
2. Edwards Syndrome (Trisomy 18; 47,XX/XY,+18):
   • Micrognathia, prominent occiput, low-set malformed faun-like ears, clenched fists with overlapping fingers (2nd over 3rd, 5th over 4th), rocker-bottom feet (prominent calcaneus), congenital heart disease (VSD, patent ductus arteriosus), severe developmental delay; <10% survive beyond 1 year.
3. Patau Syndrome (Trisomy 13; 47,XX/XY,+13):
   • Defective prechordal mesoderm development causing midline defects: holoprosencephaly, microphthalmia, cleft lip and palate, postaxial polydactyly, aplasia cutis congenita (focal punched-out scalp ulcerations), cystic renal dysplasia; median survival <7 days.

Sex Chromosome Aneuploidies

• Turner Syndrome (45,X):
  • Complete or partial absence of the second sex chromosome (50% 45,X; 20-30% mosaicism 45,X/46,XX; 10% isochromosome Xq [46,X,i(Xq)]).
  • Clinical Manifestations: Short stature (caused by haploinsufficiency of the SHOX gene in the pseudoautosomal region); ovarian dysgenesis with "streak ovaries" producing hypergonadotrophic hypogonadism (elevated FSH and LH, low oestrogen) and primary amenorrhoea; webbed neck (cystic hygroma due to lymphatic hypoplasia), low posterior hairline, shield chest with widely spaced nipples, and cubitus valgus.
  • Cardiovascular & Renal: Bicuspid aortic valve (30%), coarctation of the aorta (10%), and aortic root dilatation conferring elevated lifetime risk of aortic dissection. Renal anomalies include horseshoe kidney (which becomes trapped beneath the inferior mesenteric artery during embryogenesis). Intellect is typically normal.
• Klinefelter Syndrome (47,XXY):
  • Presence of one or more extra X chromosomes in a male phenotype due to parental meiotic nondisjunction.
  • Clinical Manifestations: Tall stature with eunuchoid proportions (increased leg length, decreased upper-to-lower segment ratio); primary testicular failure with small, firm, fibrotic testes (hyalinisation of seminiferous tubules); hypergonadotrophic hypogonadism (elevated LH/FSH, low testosterone) resulting in delayed puberty, sparse facial/body hair, and azoospermia/infertility; bilateral gynaecomastia.
  • Malignancy Risks: 20- to 50-fold increased risk of male breast cancer; increased risk of extragonadal mediastinal germ cell tumors and non-Hodgkin lymphoma; osteoporosis.

Robertsonian Translocations

Robertsonian translocations occur exclusively between the five acrocentric chromosomes: 13, 14, 15, 21, and 22. These chromosomes possess very short p-arms composed entirely of repetitive ribosomal RNA (rRNA) gene clusters.

• Mechanism: Breaks occur near the centromeres, with fusion of the long arms (q) to form a single derivative metacentric chromosome, and loss of the tiny short arms (p). Because rRNA gene clusters are reiterated on the remaining acrocentric chromosomes, loss of the p-arms produces no phenotypic consequence.
• Balanced Carrier: A balanced carrier has 45 chromosomes (e.g., 45,XX,der(14;21)(q10;q10)) and is clinically asymptomatic.
• Reproductive Risks: During meiosis, the derivative chromosome and its homologues pair as a trivalent. Alternate segregation yields normal or balanced carrier gametes. Adjacent segregation produces unbalanced gametes (monosomy 14, trisomy 14, monosomy 21, or trisomy 21). When a female carrier of a der(14;21) conceives, the empirical risk of having a live-born child with translocation Down syndrome (46,XX,+21,der(14;21)) is approximately 10-15% (compared to 1-2% if the father is the carrier, due to selective loss of unbalanced sperm). If a carrier harbors a homologous der(21;21) translocation, 100% of viable pregnancies will result in Down syndrome.