Chromosome Abnormalities Overview

Chromosome Abnormalities

• Important contributor to morbidity and mortality
• Occur in approximately 1 in 150 live births
• Leading cause of intellectual disability, pregnancy loss
  • 50% of first-trimester miscarriages
  • 20% of second-trimester miscarriages

Types of Chromosome Abnormalities

• Abnormalities in chromosome Number

  • Trisomies, Monosomies
  • Caused by nondisjunction during anaphase I or II of meiosis

• Abnormalities in chromosome structure

  • Translocations, Deletions, Duplications
  • Caused by improper chromosome recombination during prophase I of meiosis

Euploidy

• Chromosome number is a multiple of 23 (in humans)
• Includes haploid gametes and diploid somatic cells

Polyploidy

• Individuals possess an extra complete set of chromosomes (triploid, tetraploid, etc.)
• Results in seedless fruits in plants but is lethal in humans (generally)

Aneuploidy

• Total chromosome number is NOT a multiple of 23
• Monosomy: one chromosome pair is present in only one copy.
• Trisomy: one chromosome pair is present in three copies
• Autosomal monosomies are usually incompatible with life
• Autosomal trisomies can be compatible with life (trisomies 21, 18, and 13 are the most common in live births)
• “The body can tolerate excess genetic material more readily than it can tolerate a deficit of genetic material.”

Nondisjunction

• Most common cause of aneuploidy
• Occurs during meiosis, causing unequal distribution of chromosomes to daughter cells

Trisomy 21 (Down Syndrome)

• Karyotype: 47, XY, +21 (sex is irrelevant)
• Frequency: 1 in 800 to 1000 live births (most common autosomal trisomy)
• Features:
  • 5 A's of Down syndrome:
    • Advanced maternal age
    • Atresia (duodenal)
    • Atrioventricular septal defect
    • Alzheimer's disease (early onset)
    • AML (acute myeloid leukemia)
  • Accounts for 10% of intellectual disability cases in the US
  • 80% survive to age 10, 50% to age 50 with medical intervention
  • Males are usually sterile; females can reproduce but 40% fail to ovulate
  • Females with Down syndrome have a 50% risk of producing trisomic offspring, but overall risk is lowered by increased risk of spontaneous abortion

Mechanism of Trisomy 21

• 95% caused by nondisjunction, usually in the mother during meiosis I
• Mosaicism is possible, where the extra chromosome 21 is lost from some cells during early embryogenesis, leading to a milder phenotype
• Genes on chromosome 21:
  • Up to 40% have no known purpose
  • Candidate genes:
    • DYRK1A: associated with intellectual disability and learning/memory problems in mice when overexpressed
    • DSCR1 (Down syndrome critical region gene 1): overexpressed in Down syndrome fetal brains; plays a role in CNS development
    • APP: amyloid beta precursor protein; associated with some Alzheimer's disease cases

Trisomy 18 (Edwards Syndrome)

• Karyotype: 47, XY, +18
• Features:
  • SGA (small for gestational age) due to prenatal growth deficiency
  • Distinctive facial features
  • Hand abnormalities
  • Small ears and mouth
  • Short sternum
  • Congenital heart defects (especially VSDs)
  • Omphalocele
  • Diaphragmatic hernia
  • More severe developmental difficulties than Down syndrome, including inability to walk independently
• Second most common autosomal trisomy resulting in live births

Trisomy 13 (Patau Syndrome)

• Karyotype: 47, XY, +13
• Features:
  • Oral-facial clefts
  • Microphthalmia
  • Postaxial polydactyly
  • CNS, heart, and renal abnormalities
• Third most common autosomal trisomy resulting in live births

Structural Chromosome Abnormalities

• Occur due to unequal crossing over or exposure to toxic agents that cause chromosome breakage and rejoining

Types of Structural Abnormalities

• Balanced: no gain or loss of genetic material

  • Often does not affect the carrier but can cause issues in offspring
  • Examples: Translocations, isochromosomes, inversions

• Unbalanced: causes gain or loss of genetic material

  • Problematic for both carriers and offspring
  • Examples: Deletions, ring chromosomes, subtelomeric rearrangements, duplications

Translocations

• Exchange of genetic material between two nonhomologous chromosomes
• Balanced translocations:
  • Among the most common chromosomal abnormalities (up to 1 in 500)
  • Reciprocal translocations: breaks in two different chromosomes, leading to mutual exchange; carriers are often phenotypically normal.

Robertsonian Translocations

• Short arms of two nonhomologous chromosomes are lost, and the remaining long arms fuse.
• Occurs only in acrocentric chromosomes (13, 14, 15, 21, and 22)
• Carriers have 45 chromosomes but are usually phenotypically normal.

Familial Down Syndrome

• Accounts for up to 5% of Down syndrome cases.
• Result of Robertsonian translocation of 14q and 21q
• Does not have a correlation with increased maternal age.
• Risk of Down syndrome in offspring is Mendelian, meaning carriers with a Robertsonian translocation have a higher risk of passing it down.
• Typical carrier karyotype: 45, XY, der(14;21)(q10,q10)

Familial Down Syndrome without a Robertsonian Translocation

• Occurs due to isochromosome formation, where a chromosome replicates one of its arms, leading to a duplication of a specific chromosome segment and a loss of other segments.

Isochromosome

• A chromosome with two identical arms, formed as a result of misdivision of centromere during mitosis or meiosis.