Introduction

The human body is made up of trillions of somatic cells with the capacity to divide into identical daughter cells facilitating organismal growth, repair, and response to the changing environment. This process is called “mitosis.” In gamete production, a different form of cell division occurs called “meiosis.” The outcome of meiosis is the creation of four daughter cells, either sperm or egg cells, through reduction division which results in a haploid complement of chromosomes in each gamete. At fertilization, the haploid sperm cell nucleus merges with the haploid egg cell nucleus, which restores the diploid chromosomal complement and confirms the formation of the zygote. During anaphase of the cell cycle, chromosomes are separated to opposite ends of the cell to create two daughter cells. Nondisjunction is the failure of the chromosomes to separate, which produces daughter cells with abnormal numbers of chromosomes. [1][2][3]

Cellular

The genome is encoded by the chemical sequence of DNA nucleotides within our cells. In periods of cell growth, histone proteins around DNA are acetylated causing less interaction between the DNA and histone protein. This opened DNA is called euchromatin and allows transcriptional enzymes access to the DNA. Before periods of cell division, the histone proteins are deacetylated allowing for the formation of a condensed form of DNA called heterochromatin. Somatic human cells contain 23 paired chromosomes or 46 total chromosomes. Forty-six is considered the “diploid” number (2n), while 23 is considered the “haploid” number (1n) or half the diploid number. “Aneuploidy” refers to the presence of an abnormal number of chromosomes. Monosomy (n-1) is a form of aneuploidy characterized by missing a single chromosome resulting in 45 total chromosomes. Trisomy (n+1) is another form of aneuploidy that has an extra chromosome resulting in 47 total chromosomes. Each type of aneuploidy can be attributed to nondisjunction during mitosis or meiosis. [4][5][6]

Mechanism

There are 2 parts to the cell cycle: interphase and mitosis/meiosis. Interphase can be further subdivided into growth 1 (G1), synthesis (S), and growth 2 (G2). During the G phases, the cell grows by producing various proteins, and during the S phase, the DNA is replicated so that each chromosome includes 2 identical sister chromatids.

Mitosis contains 4 phases: prophase, metaphase, anaphase, and telophase. In prophase, the nuclear envelope breaks down and chromatin condenses. In metaphase, the chromosomes line up along the metaphase plate, and microtubules attach to the kinetochores of each chromosome. In anaphase, the chromatids separate and are pulled by the microtubules to opposite ends of the cell. Finally, in telophase, the nuclear envelopes reappear, the chromosomes unwind into chromatin, and the cell undergoes cytokinesis, which splits the cell into 2 identical daughter cells.

Meiosis goes through all 4 phases of mitosis twice, with modified mechanisms that ultimately create haploid cells instead of diploid. One modification is in meiosis I. Homologous chromosomes are separated instead of sister chromatids, creating haploid cells. It is during this process where we see crossing over and independent assortment leading to the increased genetic diversity of the progeny. Meiosis II progresses the same way as mitosis, but with the haploid number of chromosomes, ultimately creating 4 daughter cells all genetically distinct from the original cell.

Nondisjunction can occur during anaphase of mitosis, meiosis I, or meiosis II. During anaphase, sister chromatids (or homologous chromosomes for meiosis I), will separate and move to opposite poles of the cell, pulled by microtubules. In nondisjunction, the separation fails to occur causing both sister chromatids or homologous chromosomes to be pulled to one pole of the cell.

Mitotic nondisjunction can occur due to the inactivation of either topoisomerase II, condensin, or separase. This will result in 2 aneuploid daughter cells, one with 47 chromosomes (2n+1) and the other with 45 chromosomes (2n-1).

Nondisjunction in meiosis I occurs when the tetrads fail to separate during anaphase I. At the end of meiosis I, there will be 2 haploid daughter cells, one with n+1 and the other with n-1. Both of these daughter cells will then go on to divide once more in meiosis II, producing 4 daughter cells, 2 with n+1 and 2 with n-1.

Nondisjunction in meiosis II results from the failure of the sister chromatids to separate during anaphase II. Since meiosis I proceeded without error, 2 of the 4 daughter cells will have a normal complement of 23 chromosomes. The other 2 daughter cells will be aneuploid, one with n+1 and the other with n-1. 

Testing

In-utero, diagnosis of fetal chromosomal aneuploidy can be made by performing cytogenetic analysis of fetal cells, typically obtained through amniocentesis or chorionic villus sampling. The fetal chromosomal complement is analyzed by performing a karyotype test, counting the chromosomes, and analyzing under light microscopy, all while looking for abnormalities in chromosomal number or structure. Many prenatal screening tests exist to help provide an age-adjusted risk of fetal chromosomal aneuploidy through analysis of various markers or cell-free fetal DNA in maternal serum. [7][8]

With in vitro fertilization (IVF), testing can also be performed prior to implantation through preimplantation genetic diagnosis (PGD), polar body diagnosis (PBD), or blastomere biopsy. PGD is a technique used to identify normal embryos that will be implanted into the mother, though technologically demanding and with additional expense compared to prenatal diagnosis. PBD can detect maternally derived aneuploidies and is relatively quick to perform when compared to PGD. Lastly, a blastomere biopsy can be obtained prior to implantation for genetic analysis. However, blastomere biopsy places the developing embryo at greater risk and therefore is not currently a recommended standard of practice.

Clinical Significance

Mitotic nondisjunction can cause somatic mosaicism, with the chromosome imbalance only reflected in the direct offspring of the original cell where the nondisjunction occurred. This can cause some forms of cancer, including retinoblastoma.

Meiotic nondisjunction is of greater clinical significance since most aneuploidies are incompatible with life. However, some will result in viable offspring with a spectrum of developmental disorders.

Autosomal Trisomies

Patau syndrome: Trisomy of chromosome 13

• Clinical Features: Rocker-bottom feet, microphthalmia (abnormally small eyes), microcephaly (abnormally small head), polydactyly, holoprosencephaly, cleft lip and palate, congenital heart disease, and severe intellectual disability. Life expectancy is seldom longer than one year.

Edwards syndrome: Trisomy of chromosome 18

• Clinical Features: Rocker-bottom feet, low set ears, micrognathia (abnormally small jaw), clenched hands with overlapping fingers, congenital heart disease, and severe intellectual disability. Life expectancy is normally less than one year.

Down syndrome: Trisomy of chromosome 21

• The most common viable aneuploidy.
• Clinical Features: Single palmar crease, flat facies, prominent epicanthal folds, duodenal atresia, congenital heart disease, Hirschsprung disease, intellectual disability. Notably increased risk to develop Alzheimer's disease or leukemia. Life expectancy is about 60 years.

Sex Chromosome Trisomies

Klinefelter Syndrome: An extra X chromosome in a male (47, XXY)

• Clinical Features: Tall, long extremities, gynecomastia, female hair distribution, testicular atrophy, developmental delay.

Triple X syndrome: An extra X chromosome in a female (47, XXX)

• Clinical Features: Phenotypically normal, some with unusually tall stature.
• X chromosomes are inactivated as Barr bodies. Therefore, 2 extra Barr bodies are seen, though no clinical abnormalities result.

XYY syndrome: An extra Y chromosome in a male (47, XYY)

• Clinical Features: phenotypically normal, unusually tall stature.
• Most cases go undiagnosed due to a lack of clinical abnormalities.

Sex Chromosome Monosomies

Turner Syndrome: Monosomy of X chromosome in a female (45, X)

• The only chromosomal monosomy that is compatible with life.
• Clinical Features: Unusually short stature, shield chest, congenital heart disease, webbed neck, horseshoe kidney, ovarian dysgenesis.
• The most common cause of primary amenorrhea. No Barr bodies are seen.