Chromosomal Abnormalities

Chromosomal abnormalities are disorders caused by changes in the number or structure of chromosomes that are large enough to involve many genes at once. They include numerical changes such as trisomy and monosomy (aneuploidy) and structural changes such as deletions, duplications, translocations, and inversions. Because they typically affect dosage of many genes simultaneously, they often produce recognizable multisystem syndromes or pregnancy loss.

Definition

A chromosomal abnormality is an alteration in the normal number (e.g., trisomy, monosomy) or structure (e.g., deletion, duplication, translocation, inversion) of one or more chromosomes, usually disturbing the dosage of many genes and producing disease or developmental abnormality.

Scope

This topic covers the two broad classes of chromosomal change — numerical and structural — their principal mechanisms (chiefly meiotic nondisjunction and aberrant recombination or repair), and the way chromosomal imbalance translates into disease. It treats chromosomal abnormalities as a pathology topic; it is not a guide to prenatal screening choices or to managing any specific syndrome.

Core questions

• How do numerical abnormalities (aneuploidies) differ in mechanism and consequence from structural rearrangements?
• Why is meiotic nondisjunction the dominant origin of aneuploidy, and why does its frequency rise with maternal age?
• When is a structural rearrangement balanced and clinically silent versus unbalanced and pathogenic?
• How does gene-dosage imbalance translate into a multisystem phenotype?

Key concepts

• Aneuploidy (trisomy, monosomy)
• Nondisjunction
• Polyploidy
• Deletion and duplication
• Reciprocal and Robertsonian translocation
• Balanced versus unbalanced rearrangement
• Gene-dosage imbalance
• Mosaicism

Mechanisms

Numerical abnormalities most often arise from nondisjunction — failure of homologous chromosomes or sister chromatids to separate during meiosis — yielding gametes with extra or missing chromosomes; errors after fertilization produce mosaicism. Structural abnormalities arise from chromosome breakage and aberrant repair or recombination, producing deletions, duplications, inversions, and translocations. Balanced rearrangements preserve total genetic material and are often clinically silent in the carrier but can yield unbalanced gametes; unbalanced rearrangements change gene dosage. The phenotype usually reflects simultaneous over- or under-expression of many genes across the affected segment, as emphasized in analyses of the phenotypic impact of structural variation.

Clinical relevance

Chromosomal abnormalities account for a large share of recognized first-trimester pregnancy losses and for several well-characterized congenital syndromes, and their detection is a core function of cytogenetic laboratories. This entry explains the underlying biology for reference; it does not direct screening, diagnostic testing, or clinical management of individuals.

Epidemiology

Chromosomal abnormalities are found in an estimated majority of spontaneous first-trimester miscarriages and in roughly a small percentage of live births when balanced and unbalanced changes are combined. Trisomy 21 (Down syndrome) is the most common autosomal aneuploidy compatible with survival; sex-chromosome aneuploidies are individually less severe. The maternal-age association of nondisjunction is a consistent epidemiologic feature.

History

Human cytogenetics began when Tjio and Levan established in 1956 that humans have 46 chromosomes; within a few years trisomy 21 was identified as the cause of Down syndrome, and the major sex-chromosome aneuploidies were described. Banding techniques, and later molecular karyotyping by microarray, progressively refined the resolution at which chromosomal abnormalities could be detected.

Key figures

• Joe Hin Tjio
• Albert Levan
• Jerome Lejeune

Seminal works

• tjio-levan-1956
• weischenfeldt-2013
• roizen-2003

Frequently asked questions

What is the difference between a numerical and a structural chromosomal abnormality?

A numerical abnormality changes the count of whole chromosomes (for example trisomy 21, with three copies of chromosome 21), whereas a structural abnormality changes the architecture of one or more chromosomes through deletions, duplications, translocations, or inversions while the count may stay the same.

Why can a balanced translocation cause problems even when the carrier is healthy?

A balanced translocation keeps the total amount of genetic material normal, so the carrier is usually unaffected, but during meiosis it can produce gametes with unbalanced amounts of chromosomal material, raising the chance of miscarriage or an affected child.