Common Chromosomal Disorders (Chromosomes 1-5 and X and Y)

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Chromosomes are thread-like structures that hold genes, which are fragments of DNA that carry the hereditary information of an individual.

Chromosomes are comprised of two segments or arms separated by a region known as the centromere. The longer arm is called the "q" arm, and the shorter arm is designated as the “p” arm. A typical human cell consists of 23 pairs of chromosomes, which add up to a total of 46 chromosomes per cell. The first 22 pairs of chromosomes are called autosomes, and the last pair is called the sex chromosomes – they decide the sex of an individual. The mother and father each pass on one set of 22 autosomes and one sex chromosome to their offspring. Females have two X chromosomes (XX), and males have one X and one Y chromosome (XY).

Disorders caused by chromosomal abnormalities can be either numerical or structural.

  • A numerical disorder occurs when there is a change in the number of chromosomes. Down syndrome is a well-known example of a numerical disorder (three copies of chromosome 21).  
  • A structural abnormality results from alterations in the structure of the chromosome. Structural abnormalities may lead to a difference in the number of genes, which cause various clinical differences in affected individuals. Deletions, duplications, translocations, inversions, and rings are some of the structural abnormalities, which may lead to chromosomal disorders.
In humans, each cell normally contains 22 pairs of autosomes and one pair of sex chromosomes, X and Y, in male. - Illustration Credit: Soleil Nordic / Shutterstock
In humans, each cell normally contains 22 pairs of autosomes and one pair of sex chromosomes, X and Y, in male. - Illustration Credit: Soleil Nordic / Shutterstock

Chromosome 1

Chromosome 1 is the largest of the 23 chromosomes and consists of approximately 4,220 genes, which accounts for nearly 8% of the entire human DNA.

Chromosome 1 is highly susceptible to genetic variations such as polymorphisms or mutations, and a plethora of diseases have been linked to these abnormalities. Structural or numerical abnormalities of chromosome 1 cause the following disorders.

1p36 deletion syndrome

1p36 deletion syndrome is caused by a deletion of genetic material from the short arm or p arm of chromosome 1. The condition affects approximately 1 in 5,000 newborns and is the most common terminal chromosomal deletion in humans. The signs and symptoms depend on the extent of the deletion, which varies among the affected individuals. Some common signs of this syndrome include distinctive facial features, delay in development, intellectual disability, seizures, vision and hearing problems, congenital heart defects, and renal abnormalities.

Neuroblastoma

Neuroblastomas are cancers that initiate in immature nerve cells called neuroblasts. Deletions, within part of the short arm of chromosome 1 (1p36) are associated with the development of neuroblastoma. Researchers believe the deleted genetic portions normally contain a tumor suppressor gene; however, the exact mechanism which these genes play in cancer initiation and progression is not known.

Neuroblastoma cells: nuclei are stained in red, microfilaments are in green and in blue. Image Credit: Vshivkova / Shutterstock
Neuroblastoma cells: nuclei are stained in red, microfilaments are in green and in blue. Image Credit: Vshivkova / Shutterstock

1q21.1 microdeletion

1q21.1 microdeletion involves a change in a small piece of the long arm or q arm of chromosome 1. The exact size of the deleted region varies; however, most cases involve around 1.35 million missing DNA base pairs. Individuals with 1q21.1 microdeletion present with development delays, limitations in brain functioning, physical anomalies, and psychiatric problems; however, in some cases the patients are asymptomatic.

1q21.1 duplication syndrome

1q21.1 duplication syndrome is a chromosomal disorder caused by duplication of a small piece of chromosome 1. The syndrome is characterized by features such as large head size, developmental delay, intellectual disabilities, typical facial features, cardiac problems, and seizures. This condition can occur spontaneously or can be inherited.

Thrombocytopenia-absent radius (TAR) syndrome

Thrombocytopenia-absent radius (TAR) syndrome is a rare condition in which thrombocytopenia or low blood platelet count occurs with radial aplasia - a congenital defect characterized by abnormal forearms caused by the absence of radius bone. Most cases of TAR syndrome involve a deletion in the 1q21.1 region of chromosome 1.

Chromosome 2

Chromosome 2 is the second largest chromosomes found in human cells. Abnormalities of chromosome 2 cause the following chromosomal disorders.

2q37 deletion syndrome

2q37 deletion syndrome is a rare genetic disorder caused by the deletion of genes, at a location 2q37 of the long arm of chromosome 2. Developmental problems, intellectual and adaptive behavior problems, obesity, and bone deformities are some common signs of this condition.

Cancers

Chromosome 2 abnormalities also cause cancers such as myeloid malignancies. These abnormalities are usually somatic, which are not inherited, but rather acquired during a person's lifetime. Translocation or rearrangement of genetic material between chromosomes 2 and 3 has been held responsible for the development of myeloid malignancies.

Myelodysplastic syndrome is another condition which occurs due to chromosome 2 abnormalities. The disease affects the blood and bone marrow condition and is characterized by trisomy 2; in which cells have an extra copy of chromosome 2 than the usual two. Anemia is frequently found in people with this syndrome.

MBD5-associated neurodevelopmental disorder (MAND)

MBD5-associated neurodevelopmental disorder (MAND) is a congenital condition which leads to abnormal neurological and physical development. MAND is caused by deletion or duplication of chromosome 2 at position q23.1. MAND patients have physical deformities and intellectual disability. They also have delayed development, impaired speech, and behavioral problems.

SATB2-associated syndrome

The SATB2-associated syndrome leads to developmental delay, intellectual and behavior problems, head and face anomalies. Speech problems and dental abnormalities also occur in individuals with this syndrome. Alterations of the SATB2 gene are caused by changes on the q arm of chromosome 2

Ring chromosome

Ring chromosome is a chromosome 2 abnormality. They develop when breaks at the ends of the chromosome, join together to form a circular ring-like structure. The disorder causes developmental delay, microcephaly or small head, retarded growth, heart defects, and facial anomalies.

Chromosome 3

Chromosome 3 is the third largest chromosomes in humans, which makes up around 7% of the genetic material in the whole genome. Chromosome 3 has gene clusters that code for the receptors involved in the sense of smell and inflammatory processes. Following are some of the chromosome 3 abnormalities.

3p deletion syndrome

3p deletion syndrome is caused by deletion of genetic matter from the end of the small arm of chromosome 3. Intellectual problems, delayed development, and physical abnormalities are some features associated with this syndrome.

3q29 microdeletion syndrome

3q29 microdeletion syndrome involves the deletion of a small piece of chromosome 3 in each cell. Individuals with 3q29 microdeletion have delayed development; intellectual, behavioral and psychiatric disorders, and physical anomalies.

3q29 microduplication syndrome

As the name suggests, the 3q29 microduplication syndrome is caused due to duplication of a small piece of chromosome 3 in each cell. Signs and symptoms associated with this syndrome include delayed development and learning problems, vision problems, cardiac defects, and microcephaly.

Clear cell renal carcinoma

Clear cell renal carcinoma is associated with alterations in chromosome 3. The cancer may involve deletion of part of the p arm or translocations of genetic information or a missing chromosome copy. The changes associated with clear cell renal carcinoma are not inherited and are sporadic.

Chromosome 4

Chromosome 4 chromosome represents around 6.5% of the DNA in the human genome and comprises nearly 1000 genes. Following are some disorders caused by chromosome 4 abnormalities.

Facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy is a muscular disorder caused by hypomethylation of the D4Z4 region in the q arm of chromosome 4. Muscle weakness and muscle atrophy are two characteristic features of this disorder. The condition affects muscles of the face, arms, and shoulders. In some cases, the muscles around the eyes may also be affected.

Wolf-Hirschhorn syndrome

Wolf-Hirschhorn is a complex syndrome caused by the deletion of genetic material at a region termed 4p16.3 in the short arm of chromosome 4. The deleted part contains key genes required for normal growth and development; hence, Wolf-Hirschhorn syndrome is characterized by halted growth, intellectual disabilities, facial abnormalities, and seizures.

Cancers

Chromosome 4 abnormalities are also associated with cancers such as leukemia, multiple myeloma. Translocation or rearrangement of genetic material is held responsible for the development of these cancers.

PDGFRA-associated chronic eosinophilic leukemia is caused by alterations in the PDGFRA gene, which is located on chromosome 4. This condition is characterized by an increase in the number of eosinophils, which are a type of white blood cells involved in allergic reactions.

Chromosome 5

Chromosome 5 constitutes nearly 6% of the total DNA. Chromosome 5 has a low gene density as most of its parts have non-coding gene regions. Chromosome 5 also has genes that code for interleukins, which are modulators of immune response.

Cri-du-Chat syndrome and familial adenomatous polyposis are two conditions which are caused by deletions in chromosome 5.

Cri-du-chat syndrome

Cri-du-chat syndrome involves deletion in the short arm of chromosome 5. The condition is characterized by cat-like cry and microcephaly or small head.

Periventricular heterotopia

Periventricular heterotopia is a brain malformation caused by abnormal duplication of certain parts of chromosome 5. The disorder is characterized by abnormal neuronal migration, which leads to the accumulation of neuronal clumps or nodules around fluid-filled cavities.

Acute myeloid leukemia (AML) and Myelodisplastic syndrome (MDS)

Deletions in the long arm of chromosome 5 are often found in cancers such as acute myeloid leukemia (AML) and myelodisplastic syndrome (MDS).

Familial adenomatous polyposis

Familial adenomatous polyposis is caused by a deletion of region coding for adenomatous polyposis coli, a tumor suppressor protein, on the long arm of chromosome 5. Formation of inactive adenomatous polyposis coli leads to leads to polyps formation in the rectum and colon. Polyps are non-cancerous growths, which have a high propensity to develop into cancer.

5q31.3 microdeletion syndrome

5q31.3 microdeletion syndrome is caused by the deletion of a small piece of chromosome 5. The condition causes impaired speech and walking, low muscle tone or hypotonia, breathing problems, seizures, and facial abnormalities. Loss of the PURA gene is held responsible for most of the symptoms. Pur-alpha, the protein encoded by the PURA gene is required for normal growth or neurons.

Sex-linked chromosomes - X chromosome

X chromosome and the Y chromosome are the sex chromosomes in humans. The X chromosome represents 5% of the total DNA in women and about 2.5% of the total DNA in men. Mutations in the X chromosomes lead to several genetic disorders.

Klinefelter syndrome

Klinefelter syndrome occurs in males who have one or more extra copies of the X chromosome. Individuals with this disorder have abnormal sexual development, with impaired testes development and reduced testosterone levels. They have reduced muscle strength and decreased intellectual and motor skills. Infertility is also common.

Triple X syndrome

Triple X syndrome or trisomy X is caused by an extra copy of the X chromosome in females. Females with triple X syndrome have an increased risk of delayed development of language, motor, and cognitive skills. Even though the patients have normal fertility, problems of premature ovarian failure are quite common.

Turner syndrome

Turner syndrome is observed in females with a missing or abnormally structured X chromosome. The patients have short stature and have gonadal dysgenesis or defective gonads. Individuals with this syndrome have complications such as heart defects, bone deformities, hearing and vision problems, and kidney anomalies.

Intestinal pseudo-obstruction

Intestinal pseudo-obstruction is characterized by impairment in peristalsis – the muscle contractions that propel food through the gastrointestinal tract. The condition is caused by mutations, duplications, or deletions of the FLNA gene and the genes adjacent to the X chromosome. Intestinal pseudo-obstruction leads to accumulation of incompletely digested food in the intestines, which causes abdominal distention, pain, nausea, vomiting, and constipation or diarrhea. The condition also leads to loss of appetite and impaired absorption of nutrients.

Microphthalmia with linear skin defects syndrome

Microphthalmia with linear skin defects syndrome is caused by deletion of a region called Xp22 on the X chromosome. Microphthalmia or abnormal eyes and linear skin lesions (face and neck) are some characteristic features of the condition.

X-linked acrogigantism

X-linked acrogigantism involves duplication of GPR101 gene on the X chromosome. The condition is characterized by an enlarged pituitary gland and development of pituitary adenoma. Abnormalities in the pituitary gland lead to the excessive release of growth hormone, which, in turn, leads to rapid growth in the patients.

Sex-linked chromosomes - Y chromosome

The following chromosomal conditions are associated with abnormalities of the Y chromosome.

46,XX testicular disorder of sex development

46,XX testicular disorder of sex development is caused by translocation of the SRY gene - which is usually located on the Y chromosome, onto the X chromosome. Individuals with this disorder develop as a male despite not having a Y chromosome. They have small testes and develop gynecomastia. These individuals are infertile due to lack of sperm and have health issues related to low testosterone levels.

47,XYY syndrome

47,XYY syndrome is found in males with an extra Y chromosome in each cell. The condition causes learning disabilities, delayed speech development, and low muscle tone. Individuals with this syndrome are also taller than expected.

48,XXYY syndrome

48,XXYY syndrome develops in males with an extra X chromosome and an extra Y chromosome. The syndrome is characterized by infertility, insufficient testosterone production, cognitive and behavioral impairments, developmental delays, and an increased risk of congenital abnormalities.

Y chromosome infertility

Y chromosome infertility is characterized by azoospermia or lack of sperm cells. The condition is caused by the deletion of genetic material in areas known as the azoospermia factor or AZF region.

Sources

Further Reading

Last Updated: Jun 10, 2019

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