Chromosomal Abnormalities Lecture Review

Chromosome Classification by Centromere Position

• Chromosomes are classified based on the position of their centromere along their length.

• Metacentric Chromosome: The centromere is positioned near the middle, resulting in two chromosome arms of almost equal length.

• Acrocentric Chromosome: The centromere is placed very close to one end, leading to one very long arm and one very short arm.

• Submetacentric Chromosome: The centromere is in an intermediate position, making one arm slightly longer than the other.

Chromosome Banding Patterns

• Chromosomes are stained to reveal unique banding patterns.

• Purpose: Banding patterns are crucial for detecting deletions, duplications, and other structural abnormalities within chromosomes.

• Each major band on a chromosome is numbered in an organized manner.

Main Banding Methods

• Giemsa Banding (G-banding): This is the primary method used in clinical diagnosis to detect and study structural and numerical chromosome abnormalities.

• Q-banding: Was the first banding method developed but is rarely used in contemporary practice.

• R-banding: Utilizes heat treatment and highlights chromosome ends, producing a staining pattern that is the reverse of G-banding.

• C-banding: Specifically stains the heterochromatin regions, typically found near the centromere.

• NOR Staining: Specifically marks the satellites and stalks of acrocentric chromosomes.

• High-resolution Banding: Performed during prophase or prometaphase, stages when chromosomes are less condensed. This technique shows more detailed bands, allowing for the detection of smaller abnormalities, such as microdeletions.

Banding Notation Example

• The notation $15q12$ indicates band $12$ on the long arm ($q$) of chromosome $15$. The region number, which further subdivides the arm, is typically omitted for brevity.

Fluorescent In-situ Hybridization (FISH)

• Method: FISH employs fluorescently labeled DNA probes that bind to complementary sequences on patient chromosomes.

• Applications: It is used to detect various chromosomal abnormalities, including deletions, duplications or extra copies of chromosomal regions, and chromosomal rearrangements.

Chromosomal Abnormalities - General Overview

• Abnormalities of chromosomes can involve one or more autosomes (non-sex chromosomes), sex chromosomes, or both simultaneously.

• They are broadly categorized into three types:

  • Numerical abnormalities: Involve changes in the number of autosomes or sex chromosomes.

  • Structural abnormalities: Involve changes in the structure of chromosomes.

  • Mixoploidy: Refers to the presence of two or more cell lines with different chromosomal constitutions within the same individual.

Numerical Abnormalities

• Euploidy: A cell is considered euploid if it contains a multiple of $23$ chromosomes. This includes haploid gametes ($23$ chromosomes) and diploid somatic cells ($46$ chromosomes).

• Polyploidy: Occurs when a cell possesses an extra complete set of chromosomes.

  • In humans, the primary forms are:

    • Triploidy ($69,XXX$): Presence of three complete sets of chromosomes.

      • Causes: Can result from fertilization by a diploid sperm or a diploid egg, or by fertilization of a normal egg by two sperm (dispermy).

      • Placental Effects: Extra paternal chromosomes typically lead to a swollen placenta with hydatidiform changes, while extra maternal chromosomes usually result in a small placenta.

    • Tetraploidy ($92,XXXX$): Presence of four complete sets of chromosomes.

      • Causes: Can occur if mitosis fails in an early embryo, leading to all duplicated chromosomes being sent into a single daughter cell. It can also happen through the fusion of two diploid zygotes.

• Aneuploidy: Characterized by the gain or loss of one or more individual chromosomes (not a complete set).

  • Autosomal aneuploidies are among the most significant chromosome abnormalities.

  • Main Cause: Nondisjunction during meiosis I or meiosis II. Nondisjunction is the failure of homologous chromosomes or sister chromatids to separate properly during cell division.

  • Types:

    • Monosomy: The presence of only one copy of a particular chromosome ($2n-1$).

    • Trisomy: The presence of three copies of a particular chromosome ($2n+1$).

• Mosaicism (Numerical): This occurs when nondisjunction happens during early mitosis of a zygote, resulting in the formation of two or more different cell lines within the same individual, each with a different chromosomal constitution.

Specific Aneuploidies

Down Syndrome (Trisomy 21)

• Chromosome Abnormality: Presence of an extra copy of chromosome $21$ ($47,XX ext{ or }XY,+21$).

• Physical Features:

  • Face: Depressed nasal root, upslanting palpebral fissures (eyes slanting upwards), small and/or overfolded ears, flat maxilla and malar (cheekbone) region.

  • Hands & Muscle Tone: Approximately $50\%$ of individuals have a single palmar crease (Simian crease); hypotonia (reduced muscle tone) is common.

• Associated Genes & Effects:

  • $DYRK1A$: Overexpression due to the extra copy contributes to learning and memory defects.

  • $APP$: An extra copy of the amyloid precursor protein gene leads to early onset Alzheimer disease symptoms by around $40$ years of age.

• Other Associations:

  • Congenital heart disease.

  • Increased risk of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).

  • Intellectual disability.

Edwards Syndrome (Trisomy 18, $47,XY,+18$)

• Chromosome Abnormality: Presence of an extra copy of chromosome $18$.

• Craniofacial Features:

  • Small head with a prominent occiput (back of the skull).

  • Low-set, malformed ears.

  • Hypoplastic orbital ridges (underdeveloped bone around the eyes).

  • Short palpebral fissures.

  • Micrognathia (abnormally small chin/jaw).

• Limbs/Hands Features:

  • Characteristically clenched fists with overlapping fingers.

  • Radial aplasia (underdevelopment or absence of the radius bone in the forearm) is possible.

• Other Anomalies:

  • Omphalocele (abdominal organs protruding through the umbilical cord).

  • Diaphragmatic hernia (abdominal organs migrating into the chest).

  • Spina bifida (birth defect involving the spinal cord).

• Prognosis: Presents with severe developmental delay; most individuals do not survive past the first year of life.

Trisomy 13 (Patau Syndrome, $47,XY,+13$)

• Chromosome Abnormality: Presence of an extra copy of chromosome $13$.

• Craniofacial/CNS Features:

  • Cleft lip and/or palate.

  • Microphthalmia (abnormally small eyes).

  • Iris coloboma (a hole in the iris of the eye).

  • Microcephaly (abnormally small head).

  • Holoprosencephaly (failure of the brain to divide into two hemispheres).

  • Meningomyelocele (a severe form of spina bifida).

• Ears/Skin Features:

  • Low-set, abnormal ears.

  • Cutis aplasia (localized absence of skin, often on the scalp).

• Limbs Features:

  • Polydactyly (extra fingers or toes).

  • Clenched fists.

  • Rocker-bottom feet with prominent heels and midfoot hypoplasia.

• Other Features:

  • Cryptorchidism (undescended testes).

  • Omphalocele.

• Prognosis: Characterized by severe malformations; most affected individuals die during the neonatal period.

Klinefelter Syndrome ($47,XXY$)

• Chromosome Abnormality: Males with an extra X chromosome ($XXY$ instead of $XY$).

• Mosaicism: Approximately $15\%$ of individuals exhibit mosaicism (e.g., a mix of $XXY$ and normal $XY$ cells), which typically results in milder symptoms.

• Key Features:

  • Small testes: Leads to low testosterone levels and infertility (azoospermia).

  • Stature: Often tall with disproportionately long arms and legs.

  • Body Hair & Muscle: Less body hair and reduced muscle development compared to $XY$ males.

  • Gynecomastia: Breast tissue development occurs in some affected individuals.

  • Intelligence: Usually within the normal range, but often slightly lower than their siblings.

Turner Syndrome ($45,X$)

• Chromosome Abnormality: A condition in females characterized by the complete or partial absence of one X chromosome.

• Mosaicism: $30-40\%$ of individuals have mixed cell lines (e.g., $45,X/46,XX$ or $45,X/46,XY$), leading to a milder presentation of features.

• Key Features:

  • Stature: Short stature is a classic finding.

  • Neck: Commonly presents with a webbed neck due to redundant skin folds.

  • Chest: Broad, with a prominent sternum, is often observed in affected individuals.