Chromosomal Abnormalities: Types, Mechanisms, and Clinical Implications

Chromosomal Abnormalities

Chromosomal abnormalities refer to changes in the number or structure of chromosomes, which can lead to genetic disorders and developmental anomalies. These abnormalities are a major focus in genetics due to their impact on human health and inheritance patterns.

Chromosome Morphology

Chromosomes can be classified based on the position of their centromere, which affects their shape and behavior during cell division.

• Metacentric: Centromere is in the middle, resulting in arms of equal length.

• Submetacentric: Centromere is slightly off-center, producing one long and one short arm.

• Acrocentric: Centromere is near one end, creating a very short (p) arm and a long (q) arm.

• Telocentric: Centromere is at the very end of the chromosome (not found in humans).

Types of Chromosomal Abnormalities

Alteration of Chromosome Number

• Aneuploidy: The presence of an abnormal number of chromosomes in a cell. This includes the inheritance of an extra chromosome (trisomy) or the loss of a chromosome (monosomy).

• Polyploidy: The presence of more than two complete sets of chromosomes (rare in humans, common in plants).

Variation in Structure of Chromosomes

• Duplication: A segment of the chromosome is duplicated, resulting in extra genetic material.

• Translocation: A segment of one chromosome is transferred to another chromosome.

• Inversion: A chromosome segment is reversed end to end.

• Deletion: A segment of the chromosome is missing.

Aneuploidy

Aneuploidy is the inheritance of either an extra chromosome (trisomy) or the loss of a chromosome (monosomy). It results from errors in chromosome segregation during cell division.

• Nullisomy: Loss of one homologous chromosome pair (2n-2).

• Monosomy: Loss of a single chromosome (2n-1).

• Trisomy: One extra chromosome (2n+1).

• Tetrasomy: One extra chromosome pair (2n+2).

Table: Types of Aneuploidy

Type	Chromosome Number	Description
Nullisomy	2n-2	Loss of a homologous pair
Monosomy	2n-1	Loss of a single chromosome
Trisomy	2n+1	One extra chromosome
Tetrasomy	2n+2	One extra chromosome pair

Human Disorders Due to Chromosome Number Alterations

Autosomal Chromosome Aneuploidies

• Down syndrome: Trisomy 21

• Edwards syndrome: Trisomy 18

• Patau syndrome: Trisomy 13

Sex Chromosome Aneuploidies

• Turner's Syndrome: Monosomy X (45, X)

• Triple-X Syndrome: Trisomy X (47, XXX)

• Klinefelter's Syndrome: 47, XXY

Mechanisms of Chromosomal Abnormalities

Chromosomal abnormalities usually occur due to errors in cell division:

• Mitosis: Results in two cells that are duplicates of the original cell.

• Meiosis: Results in cells with half the number of chromosomes (gametes: ovum and sperm).

• Other factors: Maternal age and environmental influences can increase the risk of chromosomal abnormalities.

Non-disjunction of Chromosomes

• Disjunction: Normal separation of homologous chromosomes or chromatids to opposite poles during nuclear division.

• Non-disjunction: Failure of this separation, resulting in two chromosomes going to one pole and none to the other. Can occur in mitosis or meiosis.

Aneuploidy: Errors in Segregation

Nondisjunction is a failure of the separation of homologues at the first or second meiotic division, yielding cells that are missing or have extra copies of a chromosome.

Trisomy

• Most common aneuploidies in humans are trisomies.

• Trisomies are associated with a high incidence of miscarriages, except for Trisomy 13, 18, and 21, which can result in live births.

Trisomy 21 (Down Syndrome)

Down syndrome is caused by an extra chromosome 21 and is one of the most common chromosomal abnormalities in humans.

• Clinical Characteristics:

  • Duodenal atresia

  • Congenital heart disease

  • Alzheimer-like dementia

  • Intelligence varies across a wide spectrum

Diagnostic Criteria for Down Syndrome

• Hypotonia (reduced muscle tone)

• Brushfield spots on the iris

• Clinodactyly (curved 5th finger)

• Single transverse palmar (simian) crease

• Wide gap between 1st and 2nd toes (sandal gap)

Sonographic Markers

• Nuchal skinfold thickening (>2.5mm is abnormal)

• Clinodactyly

• Sandal-gap

Prenatal and Neonatal Laboratory Testing

Laboratory Test	Result/Comment
PAPP-A (Pregnancy-associated plasma protein A)	Low in pregnancy with Down syndrome fetus
Free beta hCG	Elevated in pregnancy with Down syndrome fetus
Alpha-fetoprotein (AFP)	Low in pregnancy with Down syndrome fetus
Unconjugated estriol (uE3)	Low in pregnancy with Down syndrome fetus
Inhibin A	Elevated in pregnancy with Down syndrome fetus
Karyotyping	Diagnostic; requires fetal cells from amniotic fluid, placenta, or blood

Trisomy 13 (Patau Syndrome)

• Caused by an extra copy of chromosome 13 (47, XY, +13).

• Most severe and rare; high mortality rate (>90%) with median survival of 2.5 days.

• Associated with multiple congenital abnormalities and severe cognitive impairments.

Klinefelter's Syndrome (XXY)

• Common among men (1 in 1000), but most cases are undiagnosed.

• Features: Small testes, infertility, gynecomastia, tall stature, increased leg length, hypogonadism.

• Symptoms vary: developmental delay, speech difficulties, poor motor skills.

• FSH and LH levels are high, but testosterone is low (primary gonadal failure).

Turner Syndrome

• Also called XO (45, X); only one X chromosome.

• Phenotypic females; no ovaries develop, so no puberty changes and sterility.

Table: Common Clinical Presentations of Aneuploidy

Abnormality	Birth Prevalence	Aneuploidy Risk (%)	Common Aneuploidies
Cleft lip/palate	1/1000	5–15	18, 13
Cardiac defects	5–8/1000	10–30	21; 18; 13
Duodenal atresia	1/10,000	30	21
Clubfoot	1/1000	5–30	18, 13

Diagnosis of Chromosomal Abnormalities

Amniocentesis

• Most common procedure to diagnose aneuploidy and other genetic conditions.

• Performed between 15 and 20 weeks' gestation (or later).

• Involves taking 20 mL of amniotic fluid under sonographic guidance.

Chorionic Villus Sampling (CVS)

• Performed between 10 and 13 weeks' gestation.

• Transabdominal sonography guides the catheter or needle into the early placenta.

Variation in Structure of Chromosomes

Types of Structural Aberrations

• Deletion or Deficiency

• Duplication or Repeat

• Inversion

• Translocation

Chromosomal Deletion

A chromosomal deletion indicates that a portion of a chromosome is missing, which can have significant genetic and physiological effects.

• Terminal deletion: A single break near the end of the chromosome.

• Interstitial deletion: Two breaks occur, and a section is deleted.

Cri du Chat Syndrome

• Caused by deletion of the end of the short (p) arm of chromosome 5.

• Characterized by unique facial features (epicanthic folds), microcephaly, major organ anomalies (larynx not developed), intellectual disability, and growth retardation.

• Treatment: Early intervention (physical therapy, speech therapy, behavioral modification, special education).

Prader-Willi and Angelman Syndromes

• Both involve deletion within chromosome 15q11.2.

• Prader-Willi Syndrome: Inherited from the father; features include mental retardation, obesity, short stature, and small hands/feet.

• Angelman Syndrome: Inherited from the mother; features include spontaneous laughter, jerky movements, and severe mental symptoms.

Duplication

A portion of the chromosome is duplicated, resulting in extra genetic material. This can lead to gene dosage effects and developmental abnormalities.

Translocation

Integration of a chromosome segment into a nonhomologous chromosome.

• Reciprocal translocation: Two different chromosomes exchange segments.

• Robertsonian translocation: An entire chromosome attaches to another at the centromere.

Disorders Caused by Reciprocal Translocation

• Certain cancers, such as chronic myelogenous leukemia (CML), are caused by translocations (e.g., Philadelphia chromosome: translocation between chromosomes 22 and 9).

• Myelocytic leukemia: Abnormally small chromosome 22 and new gene combinations can lead to cancer development.

Chromosomal Inversion

Inversions occur when a chromosome segment is reversed end to end. They are classified as:

• Paracentric inversion: Does not include the centromere.

• Pericentric inversion: Includes the centromere.

Example: Paracentric and pericentric inversions can disrupt gene function and lead to abnormal gametes if crossing over occurs within the inverted segment.

Additional info: Chromosomal abnormalities are a major cause of genetic disorders, miscarriages, and congenital anomalies. Early diagnosis and intervention can improve outcomes for affected individuals.