Chromosomes and Genetic Disorders
What chromosomal defect leads to what genetic disorder ?
Can we associate diseases to a deletion or a point mutation, monosomy or trisomy ?
What is the specificity of each chromosome in the human karyotype ? Let's dig...
Click on the chromosomes, title or legend to know more.
Click on another or double-click to move away.
Chromosome 4
Defects in chromosome 4 cause neurological and neurodegenerative diseases like Parkinson's disease, Huntington's disease, and narcolepsy. It also causes abnormalities in connective tissues and dwarfism.
​CONCEPT CHECK
Narcolepsy is a sleep disorder characterized by excessive sleeping, hallucinations and sleep paralysis.
Huntington's, Parkinson's and Alzheimer's diseases can be summarized with the illustration below.
Chromosome 7
It contains genes responsible for — cystic fibrosis, Pendred Syndrome and Williams-Beuren Syndrome.
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cystic fibrosis - is an autosomal recessive genetic disorder characterized by breathlessness, sinus infection, poor growth, fatty stool and infertility.
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Williams-Beuren syndrome - is characterized by an 'elfin' appearance, moderate intellectual disability, short height and overly friendly nature.
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Pendred syndrome - autosomal recessive sensorineural hearing loss condition and decreased thyroid function.
Chromosome 8
It contains genes for brain development and cancer. It has a 15 MBP region of high mutation rate, which provides evidence of the divergence of human brain from chimpanzee. Major diseases include
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Burkitt's lymphoma - is the cancer of B-lymphocytes
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Werner syndrome - is an autosomal recessive premature ageing condition, also known as adult progeria
Chromosome 6
It contains the Major Histocompatibility Complex (MHC), a cluster of 100 genes that manage immune response and are an important factor during organ transplantation.
Major diseases are mostly autoimmune, including
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Haemochromatosis - excessive intestinal absorption of dietary iron that accumulates in tissues and organs, including liver, adrenal glands, heart, skin, gonads, joints and pancreas.
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Type 1 diabetes - an autoimmune disease that affects pancreatic β cells and reduces insulin production.
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Ring 6 - mental retardation and epilepsy
Chromosome 10
It contains genes responsible for vision and retina. Major diseases include
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Refsum disease - vision loss (combined with retinitis pigmentosa) and absence of sense of smell.
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Gyrate atrophy - ocular protein metabolism disorder characterized by progressive vision loss, myopia, night-blindness and loss of peripheral vision.
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Cockayne syndrome - autosomal recessive neurodegenerative disorder with growth failure, eye disorders, abnormal sensitivity to sunlight and premature ageing.
Chromosome 11
It is the hub of (1) Ras oncogene that causes most of the cancers, and (2)about 40% olfactory receptor genes. It also has genes that cause sickle cell anemia. Major disorders include
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Sickle-cell anemia - has an abnormal haemoglobin that sickles RBCs, that causes pain, anemia, bacterial infections, swollen hands and feet, and stroke.
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Best disease - autosomal dominant progressive vision loss condition that affects macular region of retina
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Long QT syndrome - involves dangerous arrhythmias owing to long QT interval on ECG
Chromosome 13
It is an acrocentric chromosome that contains genes responsible for trisomy 13 (Patau syndrome), retinoblastoma, breast cancer and Wilson's disease.
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Patau syndrome - multiple complex organ defects during birth
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Retinoblastoma - retinal eye tumor
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Cx26 deafness - connexin 26 protein defect causing deafness
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Wilson's disease - excess buildup of copper in body (yellow rings around the cornea)
Chromosome 14
It is an acrocentric chromosome that contains genes responsible for early-onset Alzheimer's. It also contains genes for alpha-1 antitrypsin deficiency (AAT) that damages lungs and causes liver cirrhosis.
CONCEPT CHECK
Scientists have found evidence of a link between chromosomes 1, 14, 21 for early-onset and 19 for late-onset Alzheimer's.​
Chromosome 16
It is the regulatory region for aldosterone hormone, which conserves body's sodium. Major diseases include
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Crohn's disease - causes inflammation of bowel, colon and ileum
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Polycystic kidney disease - structural defects in renal tubules, causing cysts within kidneys
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Familial Mediterranean fever (FMF) - recurring fever accompanied by pain in abdomen, joints or chest
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α-Thelassemia - impaired production of hemoglobin, causing anemia
Chromosome 18
It homes genes to the second-most common trisomy - Trisomy 18, and has many genes related to structural proteins in the cell. Major diseases include
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Edwards syndrome (Trisomy 18) - clenched fists with overlapping fingers, defects in lungs, kidneys, stomach and heart, small head, small jaw
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Niemann-Pick disease - accumulation of sphingomyelin in lysosomes, leading to unsteady gait, slurry speech, difficult swallowing and abnormal posture
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De Grouchy syndrome - septal defects, defects of skull and brain
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Pitt-Hopkins syndrome - developmental defects, epilepsy, cessation of breathe
Chromosome 19
It encodes genes for apolipoprotein-E which is responsible for atherosclerosis. It also contains genes for late-onset Alzheimer's which actually causes the amyloid plaques. Major disorders include
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Severe combined immunodeficiency (SCID) - disturbed development of functional B and T cells that severely affects immunity.
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Maple syrup urine disease - sweet odored urine due to accumulation of leucine, isoleucine and valine residues, multiple behavioral changes and physiological changes
Chromosome 20
It encodes genes for adenosine deaminase deficiency, which is a form of SCID. Besides, many functional proteins have their genes on this chromosome, including growth hormone release factor (GHRF), carboxypeptidase and topoisomerase.
Chromosome 1
It is the largest human chromosome and the last to be sequenced. It is the most susceptible to single nucleotide polymorphisms (SNPs) and has one of the four oncogenes. Major genetic disorders include
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1p36 deletion - facial features, loss of intelligence
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Neuroblastoma (oncogene) - cancer of neuroblasts
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1q21.1 microdeletion - developmental delay, mental retardedness
​CONCEPT CHECK
Microdeletions are 1-3 MBP deletions that are not visible during karyotyping, but only during fluorescence labeling.
Neuroblasts are post-mitotic cells that do not divide further, but ultimately differentiate into neurons.
Chromosome 15
It contains human leukocyte antigen gene β-2 microglobulin that form the component of major histocompatibility complex II (MHC II) in forming the blood cells. Major defects include
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Prader-Willi syndrome - poor childhood feeding causing increased hunger, obesity and type 2 diabetes
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Angelman syndrome - neuronal defect, delayed development, impaired speech and balance, seizures
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Tay Sachs disease - defective gangliosides that aid in digesting fatty acids, leading to neuronal degeneration in brain and spinal cord, causing seizures, hearing loss, impaired movement and death.
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Marfan syndrome - affects connective tissues, and creates long arms, hands, fingers, overly flexible joints.
Chromosome 17
It contains Homeobox B gene cluster. It is rich in protein-coding genes and those for early-onset breast cancer, neurofibromatosis, and DNA damage response through p53 tumor-suppressor protein. Major defects include
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Charcot-Marie-Tooth disease - progressive loss of muscle tissue, high arch and claw toes, dysfunctional touch sensation owing loss of function of peripheral motor and sensory neurons
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Tumor suppressor protein p53 - the Guardian of the Genome, is any isoform of a protein that prevents cancer formation
Chromosome 22
It was the first chromosome to be fully sequenced. It is the second smallest next to chromosome 21. Major disorders include
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DiGeorge syndrome - heart and kidney problems, learning disability
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Neurofibromatosis - benign brain tumors
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Chronic myeloid leukemia - Philadelphia chromosome; white blood cell cancer
Chromosome 3
It contains olfactory receptor genes (sense of smell), and chemokine receptors that help in inflammation during an immune response. Major diseases include
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von Hippel-Lindau (VHL) disease - a rare disease that causes cysts and tumors all over the body
​CONCEPT CHECK
Chemokines are a group of signalling proteins or cytokines that induce chemotaxis in nearby cells.
Chromosome 2
It is the second largest human chromosome. It is associated with maturity-onset diabetes of the young, high blood pressure in lungs and autism. It has genes causing somatic cancer. Reciprocal translocation between chromosomes 2 & 3 cause myeloid malignancies.
Major diseases include
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bone marrow cancer (trisomy 2)
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2q37 deletion - short stature, autism
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ring chromosome 2 - short skull (microcephaly)
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partial trisomy 2 / partial monosomy 2 - delayed growth, weak muscle tone
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Waardenberg syndrome - hearing loss, pigment deficiencies, multicoloured (blue) eyes, while hairlock
​CONCEPT CHECK
Myeloid malignancies are chronic cancer of cells related to the blood and mostly derived from bone marrow.
Autism refers to a broad range of conditions characterized by challenges with social skills, repetitive behaviors, speech and nonverbal communication.
Why do chimps have 48 chromosomes and we have 46?
In the human evolutionary lineage, two ancestral ape chromosomes (2A and 2B) fused at their telomeres, producing human chromosome 2. This conclusion was made because
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chromosome 2 sequence is nearly identical to two separate chromosomes found in chimps and apes
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vestigial centromere is present in human chromosome 2
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vestigial telomeres are present in human chromosome 2
Chromosome 5
It has lowest gene density owing to greater proportion of non-coding regions. It is submetacentric, having centromere away from its usual center. 99% of chromosome 5 matches that of chimpanzees.
Major diseases include
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Cri du Chat syndrome - also called cat's cry, it is caused by deletion of portion of 5p arm; symptoms include delayed development, intellectual disability, small head size, weak muscle tone, widely set eyes, rounded face and a small jaw.
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spinal muscular atrophy (SMA) - weakened skeletal muscles and mass loss caused by loss of motor neurons present in spinal cord​
CONCEPT CHECK
Centricity of chromosomes is defined in terms of two parameters
(1) the position of the centromere
(2) number of centromere
Chromosome 9
It contains genes whose defects lead to mental retardation. Major diseases include
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chronic myeloid leukemia - cancer of white blood cells caused by translocation of chromosome 9 and 22 called Philadelphia chromosome.
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Friedrich's ataxia - an autosomal recessive condition causing impaired speech, difficulty in walking and loss of sensation in arms and legs
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Gorlin syndrome - basal cell skin cancer
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Tangier disease - highly reduced levels of high-density lipoproteins (HDL) in blood
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Tuberous sclerosis - an autosomal dominant disease that causes tumors in brain and many body organs
CONCEPT CHECK​
Philadelphia chromosome (Ph) is the chromosomal abnormality that causes chronic myeloid leukemia (CML). It is formed by an abnormally short chromosome 22 which has its genetic material (breakpoint cluster region or BCR) translocated with tyrosine protein kinase (ABL1) gene of chromosome 9. Both its discoverers belonged to Philadelphia.
Point Mutations
It is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome.
When a purine/pyrimidine is replaced by its own type, it is called transition (α), when purine is replaced by pyrimidine or vice versa, it is called transversion (β).
Chromosome 21
It encodes genes for the most common Trisomy 21 or Down Syndrome. Down syndrome is associated with delayed physical growth, characteristic facial features, and mild to moderate intellectual disability. Other defects include
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Amylotrophic lateral sclerosis - affects neurons controlling voluntary muscle movements
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Autoimmune polyglandular syndrome - autoimmune response to more than one endocrine glands
Chromosome 12
It contains Homeobox C gene cluster. Most of the genes are responsible for early birth defects. Major diseases include
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Phenylketonuria (PKU) - buildup of phenylalanine, causing musty odour, skin rashes, small head, intellectual disability, fair skin and blue eyes, and hyperactivity.
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Zellweger syndrome - absent functional peroxisomes in cells, causing mental retardation.
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Pallister-Killian mosaic syndrome - isochromosome 12p that causes birth defects and intellectual disability
CONCEPT CHECK​
Homeobox (Hox) genes are the highly conserved DNA sequences that specify regions of the body plan of an embryo along the head-tail axis of animals.
The 39 human Hox genes are located in four clusters (A-D) on different chromosomes at 7p15, 17q21.2, 12q13, and 2q31 respectively and are assumed to have arisen by duplication and divergence from an ancestral homeobox gene.
Chromosome Y
It is the sex-determining chromosome in many species. It contains the gene SRY which triggers male development, including testicles. It is one of the fastest-evolving parts of the human genome. Most of its genes are present uniquely in Y chromosome, except in XYY and XXYY aneuploidy. Major diseases include
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X-linked retinitis pigmentosa (X-RP) - affects males predominantly, since its recessive allele does not have a dominant Y counterpart. It involves pigment deposits near retina due to loss of rods and cones, leading to a tunnel vision and loss of peripheral vision. Other variants of RP are autosomal dominant and autosomal recessive.
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XYY aneuploidy - not inherited but occurs as a random event during spermatogenesis; taller than average, acne, and learning problems in males
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XXYY aneuploidy - attention deficit hyperactivity disorder (ADHD), sterility, speech impairment and developmental delays in males.
Chromosomal Deletion
When parts of chromosomes are missing, chromosomal deletion syndromes occur.
They cause birth defects and limited intellectual and physical development. In some cases, defects can lead to death during infancy or childhood.
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A few chromosomal deletion syndromes include
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Cri-du-chat syndrome
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Prader-Willi syndrome
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Wolf-Hirschhorn syndrome
Monosomy
A form of aneuploidy with the presence of only one chromosome from a pair.
If only a portion of a chromosome is missing, it is called partial monosomy.
A few monosomies are
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Cri-du-chat syndrome [5]
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Turner syndrome [X]
An example of a partial monosomy is 1p36​ deletion syndrome[1]
Trisomy
An aneuploidy with three copies of a chromosome.
If a chromosome pair fails to separate properly during cell division, the egg or sperm may end up with a second copy of one of the chromosomes. If this results in fertilization, the resulting embryo can have an entire copy of the extra chromosome, e.g. Trisomy 21 (Down Syndrome), 18 (Edwards Syndrome), 13 (Patau Syndrome), 8 (Warkani Syndrome 2).
It is further classified as
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Primary Trisomy
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Full trisomy - full chromosome is copied
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Partial trisomy - part of the chromosome is copied
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Secondary trisomy - extra chromosome is an isochromosome
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Tertiary trisomy - extra chromosome has arms from other chromosomes
Chromosome X
It is one of the two sex chromosomes in humans. It is 155 million bp long. Females have two X chromosomes, while males have one X and one Y chromosome. The X chromosome is three times the size of Y chromosome, containing about 900 genes, 55 genes for Y.
Major X linked diseases include
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Menkes syndrome - recessive copper deficiency disorder causing kinky hair, growth failure, and nervous system deterioration
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Alport syndrome - recessive kidney failure and blood in urine; more severe in males than females
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Hemophilia A - genetic deficiency in clotting factor VIII, which causes increased bleeding and usually affects males
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Fragile X syndrome - dominant intellectual disability with reduced IQ
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Rett syndrome - neurological disorder in girls, causing difficult in speaking, walking, eating and breathing, and constant repetitive hand movements
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Lesch-Nyhan syndrome - buildup of uric acid in body fluids causing gout and kidney problems, anemia, intellectual disability and self-mutilating behaviours
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X-linked SCID - recessive inability to produce T cells and NK cells of the immune system
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Duchene muscular dystrophy - recessive fatty and weak muscles that prevent walking and impair intellect
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Klinefelter syndrome (47, XXY) - is a chromosomal condition in boys and men that can affect physical and intellectual development.
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Turner syndrome (45, X0) - a short and webbed neck, low-set ears, low hairline at the back of the neck, short stature, and swollen hands and feet, ovarian malfunction
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Triple X syndrome (47,XXX or trisomy X) - tall stature, developmental delays, learning problems, and other features in some girls and women.
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Tetrachromacy - females having 4 cone cell types instead of 3 and can identify about 100 million colors
​​
CONCEPT CHECK
X-Inactivation & its Importance
In early embryonic development, one of the two X chromosomes in females is randomly and permanently inactivated or lyonized and condense into small,dense structures in the nucleus, called Barr bodies, that are used as indicators for sex. This also prevents double transcription of the same gene. This randomness ensures that X chromosome from mother is active in some cells of females, while that from the father is active in other cells.
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In pseudoautosomal regions, some genes escape X-inactivation. Usually these genes are present in both sex chromosomes and are important for development.
Genetic Disorders
A genetic disorder is a disease caused in whole or in part by a change in the DNA sequence away from the normal sequence.
Genetic disorders can be caused by
1. Mutation
1.1 Single gene
1.1.1 Autosomal dominant : one mutated gene is enough to have disease.
1.1.2 Autosomal recessive : both copies must be mutated to have disease.
1.1.3 X-linked dominant : one X chromosome must be mutated.
1.1.4 X-linked recessive : males suffer always as they have one mutated X chromosome, both copies must be mutated in females.
1.1.5 Y-linked : passed on by human males to their male offspring; rare.
1.1.6 Mitochondrial : maternally inherited diseases, often autosomal recessive.
1.2 Polygenic
1.2.1 Usually run in families, like heart disease or diabetes.
1.2.2 Environmental factors : weather, lifestyle, stress levels.
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2. Multiple factors including environmental
2.1 Combination of genotype and phenotype based on
2.1.1 Heterogeneity : the same disease can be caused by different genes or alleles.
2.1.2 Penetrance : the proportion of individuals carrying a particular allele of a gene (the genotype) that also express an associated trait (the phenotype).
2.1.3 Expressivity : the expression of particular gene by individuals having a certain phenotype.
2.2 Environmental factors
2.2.1 Disease favoring vectors : endemic or exotic
2.2.2 Invasive biota : bacteria, viruses and their hosts
2.2.3 Environmental disruptions : earthquake, floods, fire, volcanoes etc.
2.2.4 Human-derived factor : air quality, water quality, industrial wastes
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3. Chromosomal Abnormality
3.1 Numerical (Aneuploidy)
3.1.1 Monosomy : only one copy of chromosome; Turner Syndrome
3.1.2 Trisomy : 3 copies of chromosome; Down Syndrome
3.1.3 Tetrasomy : 4 copies of chromosome; Klinefelter's Syndrome
3.2 Structural
3.2.1 Deletions : Wolf-Hirschhorn syndrome [4] , Jacobsen syndrome[11q], Cri du Chat [5p]
3.2.2 Duplications : Charcot-Marie-Tooth disease type 1A [17], Pallister Killian mosaic aneuploidy [tetrasomy 12p]
3.2.3 Translocations :
3.2.3.1 Reciprocal (parts of different chromosomes) : chronic myelogenous leukemia or Philadelphia chromosome [9<>22]
3.2.3.2 Robertsonian (full chromosome attaches to centromere of another) : Down Syndrome [trisomy 21], Patau Syndrome [trisomy 13]
3.2.4 Inversions (part of chromosome breaks, turns upside down and reattaches) : polytene chromosomes.
3.2.5 Insertions (addition into the chromosome)
3.2.6 Rings (chromosomal ends fuse to form a ring) : mental retardation
3.2.7 Isochromosomes (p or q ends are removed and remaining end is mirrored across the centromere) : Turner Syndrome, neoplasia
A few common genetic diseases associated with human chromosomes are shown below. If you want to absolutely get into the details, download this.
The graph below represents the length in terms of mega base pairs (1,000,000 base pairs) and the number of genes encoded by each chromosome.
