Disorders of Incorrect Autosome Numbers

Autosomes are also known as non-sex chromosomes. A karyotype depicts the chromosomes arranged according to their sizes and centromere positions. The chromosomes are arranged into groups A to G and are known as autosomes. The sex chromosomes are named as X and Y respectively. A karyotype is a photomicrograph of chromosomes arranged in groups after the processing of the blood samples. Anomalies in chromosome structure or number may change the karyotype.

The review article discusses abnormalities associated with an abnormal number of autosomes. Abnormalities in chromosome number arise due to non-disjunction. The paired chromosomes do not separate properly. This usually happens during the metaphase of the cell division phase. Hence, it leads to abnormality in the chromosome number. This phenomenon is known as nondisjunction. It occurs either during mitosis or meiosis. There are many causes of non-disjunction. The main cause of nondisjunction is the advanced maternal age. The advancing age of the mother increases the risk of chromosomal abnormalities and nondisjunction in the zygote. There is a direct relation between suspended inactivity of the primary oocyte and the chromosomal abnormalities. Meiosis I in primary oocyte completes at the ovulation phase of the menstrual cycle. Primary oocyte remains suspended until the age of 45, after which it undergoes meiosis II. It happens as the age progresses further. As the mother’s age increases, there arises abnormality in spindle formation. Hence, it may predispose to non-disjunction. Another reason behind nondisjunction is the delayed fertilization after ovulation.

Nondisjunction is under complete genetic control. Other factors causing nondisjunction include radiation, smoking, alcoholism, excessive use of oral contraceptives, fertility drugs, pesticide exposure, and chemicals. More than 50% of spontaneous abortions arise due to either numerical or structural abnormalities in chromosomes. 1-2 % of congenital abnormalities and childhood disabilities arise due to chromosomal anomalies. The number of chromosomes helps to decide whether the cells are capable of becoming malignant. 

Image: Variations in chromosome numbers

Conditions associated with nondisjunction:

Monosomy (2N-1) is a condition in which one of the chromosomes in a pair is missing. Hence a chromosome is absent in this condition. A cell with a missing chromosome consists of 45 chromosomes instead of 46. This condition leads to monosomic disorders. During segregation stage, two chromosomes enter into a gamete, leaving the other gamete empty.

Trisomy is a condition in which the cells are diploid but contain an extra copy of the chromosome. The extra chromosome is homologous with the existing chromosome pair. Trisomy observed in autosomes is known as autosomal trisomy. Trisomy observed in sex chromosome is known as sex chromosomal trisomy. In rare cases, a phenomenon known as trisomic rescue occurs. Trisomic rescue is a condition in which trisomy occurs, but the cell loses the extra chromosome.

Polyploidy or an increase in a number of chromosomes is a condition seen in the somatic cells. The exact description of polyploidy involves an increase in the number of the haploid set of chromosomes in the cell leading to many whole sets of chromosomes. Examples include triploids, tetraploid, pentaploid, and hexaploids.

Mosaicism in autosomes is a result of nondisjunction. In this case, two or more different cell lines prevail. Thus, a chimeric tissue contains two or more genetically distinct cell types. The chromosomal constitution is different.

Incorrect centromere splitting may result into nondisjunction in anaphase. Thus, there leads to an improper separation of daughter chromosomes. Nondisjunction may also arise due to pericentromeric exchanges.

Nullisomy involves loss of a homologous chromosome pair during meiosis.

Abnormalities	Karyotype	Conditions associated with non-disjunction	Affected autosome number
Down’s syndrome (Trisomy 21)	47, XY 47, XX	Trisomy	21
Patau’s syndrome (Trisomy 13)	47, XY 47, XX	Trisomy	13
Edward’s syndrome (Trisomy 18)	47, XY 47, XX	Trisomy	18
Warkany’s syndrome (Trisomy 8)	47, XY 47, XX	Trisomy	8
Trisomy 14	47, XY 47, XX	Trisomy	14
Alfi’s syndrome (Monosomy 9)	45, XY 45, XX	Monosomy	9

Table: Abnormalities associated with an incorrect number of autosomes.

Down’s syndrome:

Trisomy 21 or Down’s syndrome is an abnormality due to trisomy of the 21^st chromosome. The chromosome 21 is an autosome. It belongs to the G group of chromosomes. These chromosomes are small, acrocentric with satellites them. Three copies of a 21^st chromosome are present. Hence, this condition is an example of trisomy. The incidence of Down’s syndrome is 1 in 700 live births and is affected by maternal age. A high number of males are affected. These individuals exhibit poor growth and developmental characteristics. They show mental retardation and poor I.Q. Heart disease and abnormal facial features are clearly visible in these patients. Mostly the trisomies, monosomies, and mosaicism lead to variations in chromosome numbers.

Trisomy 21 arises due to nondisjunction in the chromosome 21 during meiosis I in the mother. These individuals live only for sixteen to twenty years. Other reasons include Robertsonian translocation, isochromosomes, or ring chromosomes. An overexpression of gene portions on the 21^st chromosome causes half the percentage of Down's syndrome cases. Some other studies report the involvement of microRNAs too. Genetic counseling and prenatal diagnosis help to manage this condition.

Patau’s syndrome:

It is known as trisomy 13. The incidence rate is 1 in 5000 live births. There is physical and mental retardation in these children with a very less life expectancy. They may have a cleft lip or cleft palate. Such individuals are born with an extra finger or a malformed thumb. There is nondisjunction of the chromosome during meiosis. Trisomy 13 may not be inherited but arise due to spontaneous mutations. Alternatively, such cases occur due to the random events during the formation of gametes in the parents.

Edward’s syndrome:

It results due to spontaneous abortions. Mental retardation, heart defects, hearing disabilities, and abnormal tendons are peculiar features of the affected individual. An extra copy of the 18^th chromosome arises due to nondisjunction. The affected individuals exhibit microcephaly or small head, cleft lip or cleft palate, webbed toes, and abnormalities in fingers.

Warkany’s syndrome:

It is also known as trisomy 8 with or without mosaicism. It accompanies RECQL4 helicase disorder. These individuals are affected with telangiectasia, atrophies, and malignancies. Chronic myeloid leukemia with a bcr-abl fusion gene may also accompany trisomy 8.

Trisomy 14:

The condition results in an extra copy of the 14^th chromosome. It results in craniofacial malformations, microphthalmia, palpebral fissures, low set ears, and an abnormal cleft and palate. Trisomy 14 mosaics have hyperpigmentation, genital malformations, cryptorchidism, and asymmetric limbs.

Alfi’s syndrome:

It arises due to monosomy of the 9^th chromosome. It accompanies micro genitalia and microcephaly. It is also known as 9p deletion syndrome. It is a rare genetic disorder. It leads to mental retardation and physical defects.

Tetrasomy 12p syndrome:

It is known as Pallister-Killian syndrome. It is a rare multiple congenital anomaly with mosaicism. It is involved in an extra chromosome 12p (isochromosome). This condition leads to tetrasomy. A prenatal diagnostic technique such as chorionic villus sampling is efficient in detecting this condition.

References:
[1] Medical Genetics,  Lynn B. Jorde, John C. Carey
[2] Emery's Elements of Medical Genetics, Peter D Turnpenny, Sian Ellard
[3] Trisomy 8- Wikipedia
[4] Monosomy 9p- Wikipedia
[5] Tetrasomy 12p- Wikipedia

© Copyright, 2018 All Rights Reserved.