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StatPearls . Endowment Island (FL): StatPearls Publishing; 2021 Jan-.


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Genetics, Nondisjunction

Samantha F. Gottlieb; Connor Tupper; Connor C. Kerndt; David H. Tegay.

Author Information

Introduction

The human being body is made up of trillions the somatic cells v the capacity to division into identical daughter cell facilitating organismal growth, repair, and an answer to the transforming environment. This procedure is called “mitosis.” In gamete production, a different form of cell division occurs referred to as “meiosis.” The outcome of meiosis is the production of 4 daughter cells, one of two people sperm or egg cells, with reduction division which outcomes in a haploid match 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 development of the zygote. During anaphase that the cabinet cycle, chromosomes space separated come opposite ends of the cabinet to develop two daughter cells. Nondisjunction is the failure of the chromosomes to separate, i m sorry produces daughter cells through abnormal numbers of chromosomes. <1><2><3>


Cellular

The genome is encoded through the chemical sequence of DNA nucleotides within our cells. In durations of cell growth, histone proteins around DNA room acetylated bring about less interaction between the DNA and histone protein. This opened DNA is dubbed euchromatin and allows transcriptional enzymes accessibility to the DNA. Prior to periods of cell division, the histone proteins room deacetylated allowing for the development of a condensed form of DNA dubbed heterochromatin. Somatic human being cells contain 23 combine chromosomes or 46 total chromosomes. Forty-six is thought about the “diploid” number (2n), while 23 is taken into consideration the “haploid” number (1n) or fifty percent the diploid number. “Aneuploidy” describes the presence of one abnormal variety of chromosomes. Monosomy (n-1) is a form of aneuploidy characterized by absent a single chromosome bring about 45 total chromosomes. Trisomy (n+1) is another type of aneuploidy that has one extra chromosome causing 47 complete chromosomes. Each form of aneuploidy can be attributed come nondisjunction throughout mitosis or meiosis. <4><5><6>


Mechanism

There are 2 components to the cell cycle: interphase and also mitosis/meiosis. Interphase deserve to be additional subdivided into expansion 1 (G1), synthesis (S), and growth 2 (G2). Throughout the G phases, the cabinet grows by producing various proteins, and during the S phase, the DNA is replicated so the each chromosome includes 2 similar sister chromatids.

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

Meiosis goes through all 4 phases the mitosis twice, with modified mechanisms that ultimately create haploid cells instead of diploid. One change is in meiosis I. Homologous chromosomes are separated instead of sisters chromatids, producing haploid cells. That is throughout this procedure where we see crossing over and independent assortment causing the increased genetic diversity that the progeny. Meiosis II progresses the same method as mitosis, yet with the haploid number of chromosomes, ultimately developing 4 daughter cells all genetically unique from the initial cell.

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

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

Nondisjunction in meiosis I occurs when the tetrads fail come separate throughout anaphase I. At the end of meiosis I, there will certainly be 2 haploid daughter cells, one v n+1 and the other with n-1. Both of this daughter cells will certainly then walk on to divide once an ext in meiosis II, producing 4 daughter cells, 2 with n+1 and also 2 v n-1.

Nondisjunction in meiosis II outcomes from the failure of the sister chromatids come separate during anaphase II. Because meiosis i proceeded there is no error, 2 of the 4 daughter cells will have actually a normal enhance of 23 chromosomes. The various other 2 daughter cells will certainly be aneuploid, one with n+1 and the other with n-1. 


Testing

In-utero, diagnosis that fetal chromosomal aneuploidy can it is in made by performing cytogenetic evaluation of fetal cells, generally obtained v amniocentesis or reasonable villus sampling. The fetal chromosomal enhance is analyzed by performing a karyotype test, counting the chromosomes, and analyzing under irradiate microscopy, all while looking for abnormalities in chromosomal number or structure. Numerous prenatal screening test exist come help carry out an age-adjusted threat of fetal chromosomal aneuploidy through evaluation of miscellaneous markers or cell-free fetal DNA in maternal serum. <7><8>

With in vitro fertilization (IVF), experimentation can additionally be performed before implantation v preimplantation hereditary diagnosis (PGD), polar human body diagnosis (PBD), or blastomere biopsy. PGD is a method used to recognize normal embryos that will certainly be implanted right into the mother, despite technologically demanding and with extr expense compared to prenatal diagnosis. PBD have the right to detect maternally acquired aneuploidies and is reasonably quick to perform when contrasted to PGD. Lastly, a blastomere biopsy can be obtained before implantation for genetic analysis. However, blastomere biopsy locations the developing embryo at higher risk and therefore is not currently a recommended standard of practice.


Clinical Significance

Mitotic nondisjunction can cause somatic mosaicism, v the chromosome imbalance only reflected in the straight offspring that the original cell whereby the nondisjunction occurred. This can reason some forms of cancer, including retinoblastoma.

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

Autosomal Trisomies

Patau syndrome: Trisomy that chromosome 13


Clinical Features: Rocker-bottom feet, microphthalmia (abnormally tiny eyes), microcephaly (abnormally tiny head), polydactyly, holoprosencephaly, slot lip and palate, congenital love disease, and severe intellectual disability. Life expectancy is seldom longer than one year.
Clinical Features: Rocker-bottom feet, low set ears, micrognathia (abnormally tiny jaw), clenched hands through overlapping fingers, congenital love disease, and also severe pundit disability. Life expectations is normally less than one year.
Clinical Features: solitary palmar crease, level facies, prominent epicanthal folds, duodenal atresia, congenital heart disease, Hirschsprung disease, pundit disability. Notably raised risk to develop Alzheimer"s condition or leukemia. Life span is around 60 years.
Clinical Features: Tall, long extremities, gynecomastia, woman hair distribution, testicular atrophy, developmental delay.
X chromosomes space inactivated as Barr bodies. Therefore, 2 extra Barr bodies are seen, though no clinical abnormalities result.

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Clinical Features: Unusually short stature, shield chest, congenital love disease, webbed neck, horseshoe kidney, ovarian dysgenesis.