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,whichrestores 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. Nondisjunctionis 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 allowstranscriptional 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-sixis 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 thathas 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 chromosomeincludes 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. hom*ologous 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 hom*ologous 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 hom*ologous chromosomes to be pulled to one pole of the cell.
Mitotic nondisjunction can occurdue 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).
Nondisjunctionin meiosis Ioccurs whenthe 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 aneuploidycan 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, andanalyzingunder light microscopy, all while looking for abnormalitiesin 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 expensecompared to prenatal diagnosis. PBD can detect maternally derived aneuploidies and is relatively quick to perform when compared to PGD. Lastly, a blastomere biopsy can beobtained 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 thanone year.
Down syndrome: Trisomy of chromosome 21
The most common viable aneuploidy.
See AlsoCell DivisionClinical 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 areseen.
References
- 1.
Kaser D. The Status of Genetic Screening in Recurrent Pregnancy Loss. Obstet Gynecol Clin North Am. 2018 Mar;45(1):143-154. [PubMed: 29428282]
- 2.
Skuse D, Printzlau F, Wolstencroft J. Sex chromosome aneuploidies. Handb Clin Neurol. 2018;147:355-376. [PubMed: 29325624]
- 3.
Kurtas NE, Xumerle L, Leonardelli L, Delledonne M, Brusco A, Chrzanowska K, Schinzel A, Larizza D, Guerneri S, Natacci F, Bonaglia MC, Reho P, Manolakos E, Mattina T, Soli F, Provenzano A, Al-Rikabi AH, Errichiello E, Nazaryan-Petersen L, Giglio S, Tommerup N, Liehr T, Zuffardi O. Small supernumerary marker chromosomes: A legacy of trisomy rescue? Hum Mutat. 2019 Feb;40(2):193-200. [PubMed: 30412329]
- 4.
Ushijima K, Yatsuga S, Matsumoto T, Nakamura A, f*ckami M, Kagami M. A severely short-statured girl with 47,XX, + 14/46,XX,upd(14)mat, mosaicism. J Hum Genet. 2018 Mar;63(3):377-381. [PubMed: 29311684]
- 5.
Saito TT, Colaiácovo MP. Regulation of Crossover Frequency and Distribution during Meiotic Recombination. Cold Spring Harb Symp Quant Biol. 2017;82:223-234. [PMC free article: PMC6542265] [PubMed: 29222342]
- 6.
Li X, Liu Y, Yue S, Wang L, Zhang T, Guo C, Hu W, Kagan KO, Wu Q. Uniparental disomy and prenatal phenotype: Two case reports and review. Medicine (Baltimore). 2017 Nov;96(45):e8474. [PMC free article: PMC5690727] [PubMed: 29137034]
- 7.
Coppedè F. Risk factors for Down syndrome. Arch Toxicol. 2016 Dec;90(12):2917-2929. [PubMed: 27600794]
- 8.
Soellner L, Begemann M, Mackay DJ, Grønskov K, Tümer Z, Maher ER, Temple IK, Monk D, Riccio A, Linglart A, Netchine I, Eggermann T. Recent Advances in Imprinting Disorders. Clin Genet. 2017 Jan;91(1):3-13. [PubMed: 27363536]
