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Transcript of Chromosomal Abnormalities
She and her husband, Andre, have two older sons, Marcos, 19, and Esteban, 17
Marcos graduated from high school on time
Esteban in his 10th grade in school has looked a bit taller than his brother and has had developmental delays, social awkwardness and learning disabilities as a baby and toddler
Omyra, Andre and Marcos had no unusual health problems
Omyra’s doctor asked her to take Amniocentesis and based on the results from fetal chromosomes, a geneticist from the hospital suggested that all family members have chromosome tests
A chromosomal abnormality was detected in the unborn Maribella that also explained Esteban’s condition Esteban's Story Resources Used:
Medical Genetics; 4th Ed, Jorde et al. Mosby Elsevier
Human Genetics; 8th Ed, Lewis, R. McGraw Hill Learning Objectives Cytogenetic Technology Chromosome Banding
Fluorescence in situ Hybridization (FISH)
Comparative Genomic Hybridization (CGH) Chromosome Banding Staining of chromosomes with dyes to identify chromosomes and detect deletions, duplications and other structural abnormalities
Quinacrine (Q-banding), Giesma (G-banding), C-banding, nucleolar organizing region stains (NOR stains) and high-resolution banding Fluorescence in situ Hybridization
A fluorescent DNA probe from human chromosome is hybridized to metaphase, prophase or interphase chromosomes
Fluorescent microscope is used to detect the hybridization to specific locations
FISH is used to detect deletion, addition of chromosomes or chromosomal regions as well as rearrangements within chromosomes
Multiples probes can also be used targeted to detection of various conditions simultaneously – spectral karyotyping (SKY) Spectral Karyotyping Comparative Genomic Hybridization (CGH) CGH is used to detect deletions or duplications of DNA on chromosomes or microarrays of BACs or oligonucleotides
Microarrays provides 5-10X better resolution and has the ability to detect 1 Mb or about 50 Kb deletions or duplications
The most powerful of the three procedures
CHG cannot be used for translocations or inversions Chromosomal Abnormalities Abnormalities of Chromosome Number Euploidy - Refers to cells whose chromosome number is a multiple of 23 (in humans) such as haploid gametes (23,X), diploid somatic cells (46,XX) and triploid cells (69, XXX)
Aneuploidy – The condition in which the number of chromosomes is not a multiple of 23. For example, trisomy 18 (47, XY+18). Euploidy
Triploidy (69,XXX) and tetraploidy (92,XXXX) have been
observed in humans
Triploidy may result from dispermy, fusion of egg and
polar body before fertilization or meiotic failure resulting
into diploid sperms or eggs
Tetraploids may result from mitotic failure in early
embryo or fusion of two diploid zygotes
Triploids are generally lost in the first two trimesters
and tetraploids have been seen only in 5 live births Aneuploidy Aneuploids are missing or have additional individual chromosomes, e.g., monosomy (45 chromosomes) or trisomy (47 chromosomes)
Aneuploidy is caused by the fusion of gametes with unequal number of chromosomes resulted from nondisjunction during meiosis
There are two types of aneuploidies; autosomal and sex chromosome Aneuploidy Autosomal Aneuploidy - Monosomies are almost always lethal, some autosomal monosomies are compatible with survival
Trisomy 21 (47, XY, +21 or 47, XX, +21) is called Down syndrome
Trisomy 18 (47, XY, +18) is known as Edwards syndrome
Trisomy 13 (47, XY,+13) also termed as Patau syndrome
Sex Chromosome Aneuploidy - Consequences of these aneuplodies are less severe probably because of X inactivation
Turner syndrome (45, X0)
Klinefelter syndrome (47, XXY)
Triplo X (47, XXX)
Jacob syndrome (47, XYY) Abnormalities of Chromosome Structure Chromosomal rearrangement as a result of loss or duplication of a part of a chromosome during gamete formation
There are two types of structural abnormalities;
Balanced – rearrangement causes no loss or gain of chromosomal material
Unbalanced - rearrangement causes loss or gain of chromosomal material
Structural abnormalities, especially unbalanced, can produce serious disease in individuals and their offspring
Chromosomal alterations can occur due to;
Unequal crossing over during meiosis
Chromosomal breakage during meiosis or mitosis Translocations Translocations – interchange of genetic material between nonhomologous chromosomes. There are two types of translocations;
- Reciprocal, and
Reciprocal – two different chromosomes break and mutually exchange genetic material
The carrier of reciprocal translocation is usually unaffected
The offspring may be unaffected or may have genetic deletions (partial monosomy) or duplications (partial trisomy) Translocations RobertsonianTranslocations – short arms of nonhomologous chromosomes are lost and long arms fuse at centromere to make a single chromosome
Confined to acrocentric chromosomes, 13, 14, 15, 21 and 22
Loss of short arm may not be significant
Carrier are usually phenotypically normal
Offspring may inherit an extra or missing long arm of one chromosome Deletions & Microdeletions Loss of genetic material from a chromosome;
Terminal – loss of a part of the chromosome from one end
Interstitial – loss of a part of the chromosomes that results from two breaks in the chromosomes
Most common chromosomal abnormalities after the three autosomal aneuplodies
Cri-du-chat syndrome [(46, XX/XY, del (5p)]
Wolf-Hirschhorn syndrome [(46, XX/XY, del (5p)]
Microdeletion syndromes multiple types, e.g., Prader-Willi [(46, XX/XY, del (15q11-13)], DiGeorge [(46, XX, del (22q11)], Deletion 1p36 [46,XX/XY del (1p36)], Williams [(46, XX, del (7q1)] and others Ring Chromosome Deletions of both tips of a chromosome and subsequent fusion results in ring chromosomes
Such chromosomes are often lost causing monosomy
Some diseases are attributed to ring chromosomes, e.g., cat eye syndrome due to small chromosome 22 ring Isochromosome A chromosome with two identical arms due to parting of centromeres in the wrong plane
Known for chromosomes 12 and 21 as well as for long arms of the X and Y chromosomes
Babies with isochromosomes Xq usually have features of Turner syndrome and 18q Edward syndrome Inversions Result from two breaks to a chromosome followed by reinsertion to the original place but inverted
Carrier usually has no disease but the off spring can have deletion or duplications
It some case of chromosome 8 inversions it causes mental retardation, heart defects, seizures and facial appearance Summary Chromosomal aberrations induce patterns of malformations, anomalies and phenotypes. Individual features may vary and be non-specific.
Most abnormalities are associated with developmental delays in children and metal retardations in adults
Most syndromes involve alterations of facial morphogenesis
Growth delay is commonly seen
Congenital malformations occur in increased frequency, AV canals and VSDs are common in children with Down syndrome MUHAMMAD A. LODHI, PHD. The Chromosomal Basis of Human Disease Q1. Quick diagnosis of Esteban and his unborn sister, Maribella.
Q2. Why does a metaphase chromosome look like a thick ‘X’?
Q3. Why CHG cannot be used to detect translocations or inversions?
Q4. What is nondisjunction during meiosis?
Q5. When was the human genome sequencing project completed?
a. 2003 b. 2005 c. 2007
Q6. What type of chromosomal rearrangement is seen in Esteban and Maribella?
a. Robertsonian translocation of 10q and 17q
b. Partial trisomy of 17q
c. Inversion between 10q and 17q
Q7. Aneuploidies indicate that human genome has less tolerance for excessive amount of genetic material?
(True / False)
Q8. What is the name of the discipline of science in which division is the same thing as multiplication and even cleavage? Today's Questions Centromere Telomere NOR Alu Probes used for Karyotyping (50%) (0.65%) Today’s lecture
Methods utilized to detect different chromosomal conditions
Types of chromosomal abnormalities and their effects
Small Group Discussion & Journal Club
Aneuploidies and Deletions (4 papers)
OMIM database (hands on demonstration)
CGH/Microarrays (1 paper) Aradhya S and Cherry AM. 2007. Array-based comparative genomic hybridization. Genet Med. 9:553-9
Kobrynski LJ and Sullivan KE. 2007. Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet, 370:1443-52
Loscalzo ML. 2008. Turner Syndrome. Pediatr Rev. 29:219-27.
Stankiewicz P and Beaudet AL. 2007. Use of array CGH in evaluation of dysmorphology, malfunctions, developmental delays, and idiopathic mental retardation. Curr Opin Genet Dev. 17:182-92
Wattendorf DJ and Muenke M. 2005. Klinefelter syndrome. Am Fam Physician, 72:2259-62. List of the Papers Ring chromosomes result from the deletions of the both tips of the chromosomes
Isochromosome is a chromosome with two identical arms due to parting of centromeres in the wrong plane
Inversions result from two breaks to a chromosome followed by reinsertion to the original place but inverted
Other Abnormalities ? ? ? ? ?