Aneuploidy

Aneuploidy is the presence of an abnormal number of chromosomes in a cell, differing from an exact multiple of the haploid set. It is the most common class of clinically significant chromosomal abnormality in humans and the leading identified genetic cause of pregnancy loss and of congenital syndromes such as Down syndrome. This area orients the reader to the gain or loss of whole chromosomes and to the meiotic and mitotic errors that produce them.

Definition

Aneuploidy is a chromosome complement that is not an exact multiple of the haploid number because one or more whole chromosomes are present in extra copies or are missing, in contrast to euploidy (a balanced multiple of the haploid set) and to polyploidy (whole extra chromosome sets).

Scope

The area covers numerical chromosome abnormalities as a group: the basic vocabulary (euploidy, aneuploidy, trisomy, monosomy, nullisomy), the cellular mechanisms that generate them (chiefly meiotic nondisjunction), and the major clinical and reproductive consequences. Its child topics treat trisomy and trisomy disorders, monosomy and Turner syndrome, and polyploidy. It is positioned as a methodological and reference overview within cytogenetics, not as clinical guidance.

Sub-topics

• monosomy and turner syndrome
• polyploidy
• trisomy and trisomy disorders

Core questions

• What cellular errors generate an abnormal chromosome number, and at which stage of cell division do they arise?
• Why is maternal age the strongest known correlate of human aneuploidy?
• Why are most autosomal aneuploidies lethal before or around birth while some are compatible with survival?
• How does aneuploidy of sex chromosomes differ in tolerance and phenotype from autosomal aneuploidy?

Key concepts

• Euploidy versus aneuploidy
• Trisomy, monosomy, and nullisomy
• Meiotic nondisjunction
• Mitotic nondisjunction and anaphase lag
• Mosaicism
• Maternal-age effect
• Gene dosage imbalance
• Sex-chromosome versus autosomal aneuploidy

Mechanisms

Most human aneuploidy arises from nondisjunction, the failure of paired homologous chromosomes or sister chromatids to separate during cell division, so that one daughter cell receives an extra chromosome and the other receives one too few. Errors in maternal meiosis I predominate and are strongly associated with advancing maternal age, a relationship attributed in part to the prolonged arrest of human oocytes and to weakened cohesion and recombination over time. Errors can also occur in meiosis II, in paternal meiosis, or post-zygotically in mitosis, the last producing mosaic cell lines. The resulting imbalance in gene dosage disturbs development; the degree of disruption depends on which chromosome is affected and on the number and identity of the genes carried on it.

Clinical relevance

Aneuploidy underlies a large share of recognised chromosomal disorders and of spontaneous miscarriage, and detecting it is a central aim of prenatal screening and diagnostic cytogenetics. This entry describes the concept and its biological basis as background for evidence appraisal; it is not a basis for individual diagnostic or reproductive decisions.

Epidemiology

Aneuploidy is common at conception but is heavily selected against in early development, so it is far more frequent in spontaneous abortions than in liveborn infants. Its incidence rises sharply with maternal age. Among liveborns, trisomy 21 is the most frequently observed autosomal aneuploidy, while sex-chromosome aneuploidies are collectively common and often milder.

History

The recognition that an abnormal chromosome number causes human disease dates to 1959, when trisomy of chromosome 21 was identified as the basis of Down syndrome and monosomy X as the basis of Turner syndrome, shortly after the correct human chromosome count of 46 was established. Subsequent decades clarified that nondisjunction in meiosis is the principal source of aneuploidy and documented the strong maternal-age effect, work synthesised in later reviews of the genesis of human aneuploidy.

Key figures

• Terry Hassold
• Patricia Hunt
• Jerome Lejeune

Seminal works

• hassold-hunt-2001
• nagaoka-2012

Frequently asked questions

What is the difference between aneuploidy and polyploidy?

Aneuploidy is a gain or loss of one or a few individual chromosomes (for example, three copies of chromosome 21), whereas polyploidy is the presence of one or more complete extra sets of chromosomes (for example, 69 chromosomes instead of 46).

Why does the chance of aneuploidy increase with maternal age?

Human oocytes remain arrested in meiosis for many years, and the molecular machinery that holds chromosomes together and segregates them is thought to deteriorate over time, making nondisjunction more likely in older eggs.