M2C: Chromosomes And Disease

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Chromosomal Disorders

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Arise from changes in number or structure of chromosomes. Change in amount of arrangement of genetic material can lead to problems in growth, development, or function of body systems. Can happen during production of germ cells or early after the baby's conception. Can also be inherited from parents.

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Aneuploidy

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An abnormal chromosomal number.

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Trisomy

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An abnormal chromosome complement with an extra chromosome. Ex: Trisomy 21 (causes Down's).

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Monosomy

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An abnormal chromosome complement with a missing chromosome. Ex: 45X (Turner's Syndrome).

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Triploidy

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Abnormal chromosome complement with an extra of each chromosome. Usually caused by fertilization by more than one sperm. Almost invariably leads to death during gestation or immediately following birth.

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Deletion

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Loss of a section of DNA within a chromosome.

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Duplication

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Gain of a segment of DNA within a chromosome.

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Inversion

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Structural change in which a segment of DNA is oriented opposite from normal.

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Translocation

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Structural change in which a segment of DNA is located in the wrong place. Either on same or different chromosome.

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Ring Chromosome

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Abnormal chromosome formed by breakage and fusion to form a ring structure.

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Clinical Cytogenetics

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Study of chromosomes, their structure and inheritance. Female is 46XX, male is 46XY. Clinical laboratory methods are used to detect changes in chromosomal number and structure. Mitosis can be studied in several cells, meiosis is more difficult.

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Centromere Position and some nomenclature

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1. Metacentric: arms nearly equal
2. Submetacentric: arms are a little un-equal.
3. Acrocentric: centromere near the end.
Short arms are p. Long arms are q.

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Chromosome positioning regions

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Each chromosome arm is divided into regions labled p1, p2, q1, q2, etc. counting outward from centromere. Regions divided into bands and sub-bands labeled p1.1, p15.3, etc. Note p11.1 is said "p one one point one". Proximal means near to centromere, Distal means farther from centromere.

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Chromosome identification

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IDed by size, centromere position, and banding pattern.

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Chromosome Banding (Karyotyping)

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G-banding. Chromosomes are subjected to digestion with trypsin and stained with Giemsa (DNA dye). Dark bands are known as G-bands (condensed chromatin), pale bands are G-negative (gene rich and less tightly wound). R and Q banding methods are seldom used. Have 450-850 visible bands/chromosome depending on resolution of test. More bands = more abnormality detection possible. Can detect structural changes on the 5-10 Mb scale depending on resolution of banding.

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Molecular Cytogenetics Techniques

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1. Fluorescence in Situ Hybridization (FISH)
2. Chromosome Paint
3. Spectral Karyotyping (SKY)
4. Array-comparitive genomic hybridization

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Fluorescence in Situ Hybridization (FISH)

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Specific probes to examine presence/absence of specific DNA sequence. Usually on mitotic chromosomes (requires living sample). Each assay is FISH probe specific and can detect large structural changes.

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Chromosome Paint

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Mix of single copy DNA sequences that are specific for a chromosome and hybridize along its length.

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Spectral Karyotyping (SKY)

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24 individual chromosome painting probes labeled with different fluorescent dyes and used as a total genome chromosome paint. Fluorescent signals are then analyzed by a computer.

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Array-comparative genomic hybridization

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Microarrays are spotted with millions of specific DNA probes while pt's DNA is fluorescently labeled and hybridized to a "chip" for analysis of gains/losses. Rapid and sensitive and detects all unbalanced abnormalities. Fails to detect balanced abnormalities or inversions. Becoming very common.

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Common causes of chromosomal aberration

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1. Misrepair of broken chromosomes.
2. Improper recombination in meiosis or mitosis (unequal crossing over).
3. Mal-segregation of chromosomes in mitosis/meiosis.

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Chromosomal Abnormality Nomenclature

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Constitutional abnormality is present in all cells of the body.
Somatic of fractional abnormality is present in only a fraction of cells or tissues.
Mosaicism is a condition in which an individual possess two or more genetically different cell lines derived from a single zygote.

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Incidence of Chromosome Abnormalities

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The general incidence of chromosomal abnormalities in newborns is ~1:150. Responsible for 40-50% of spontaneous miscarriages. Trisomy16 accounts for 1/3 of trisomies in spontaneously aborted fetuses.

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Euploid

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Refers to having the exact multiple of the haploid number.

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Tetraploidy

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4n. Usually results from failure of completion of a zygotic cleavage. These fetuses do not survive.

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Trisomy 21

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Down's Syndrome. 1866 by Dr. John Langdon Down. Worked with people with intellectual disabilities and noticed physical similarities between them. Can also be caused by inheritance of Robertsonian Translocation on chromosome 21.

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Trisomy 18 and Trisomy 13

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Trisomy 18 is Edward's Syndrome, and Trisome 13 (Patau Syndrome) are trisomies that cause severe birth defects and developmental disabilities. Individuals with these trisomies generally do not live past infancy. Survival into child/adulthood is more common now due to surgery, respiratory, and nourishment advancements. These individuals usually have profound mental retardation.

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Mosaic Aneuploidy

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Other than 21, 18, and 13, all trisomies of autosomal chromosomes are not compatible with life. Mosaic aneuploidy of almost any autosome, however, carries a much milder phenotype and is generally survivable.

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Sex Chromosome Abnormalities

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Among the most common aneuploidies. Phenotypes tend to be less severe than autosomal aneuploidies.

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Klinefelter Syndrome

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Associated with an extra X chromosome in a male (XXY). Male phenotype due to presence of testis determining factor (SRY) from Y. More rare is XXXY. First described by Dr. Klinefelter in 1942 and is caused by problem in cell division at conception or soon after. Incidence is ~1/1000.

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Turner Syndrome

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45,X/monosomy X. Missing X chromosome in a female. Characteristic phenotype of short stature, cardiovascular defects, impaired sexual development and infertility. Incidence is ~1:2000-1:5000. Can also have mosaic Turner Syndrome. Can also be caused by structural problem on second X chromosome. Ring forms, inversions, deletions, etc. Is cause of ~20% of spontaneous abortions with aneuploidy.

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Other sex chromosome aneuploidies

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XYY Syndrome and "Triple X Syndrome, or XXX.

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Structural Rearrangements

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Effect part of a chromosome but do not change the overall number of chromosomes. Large rearrangements usually result from breakage followed by a reconstitution to an abnormal configuration.

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Unbalanced Rearrangement

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Involves gain or loss of genetic material and generally results in a phenotype effect.

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Balanced Rearrangement

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Does not involve a loss of gain of genetic material. Can involve strand breakage or disruption in a gene, however, leading to mutations.

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Inversions

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Segment of chromosome that is present in opposite orientation from normal. Pericentric inversions include the centromere. Paracentric inversions do not include the centromere.

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Reproductive Considerations with inversions

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Risk of abnomal offspring in a carrier of a paracentric inversion is rare because resultant chromosomal abnormalities are so severe that they are incompatible with viable development. Paricentric inversions can lead to unbalanced gametes with both chromosomal gains and losses after crossing over. 5-10% risk of this unbalanced karyotype. Degree of phenotype severity depends on size of inversion and amount of deleted/duplicated material.

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Translocation

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Rearrangment of genetic material between two or more chromosomes. Intrachromasomal translocation is rearrangement between homologs. Interchromosomal translocations is rearrangments between non-homologous chromosomes (more common).

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Reciprocal Translocations

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The most common type of translocation. Genetic material is swapped between non-homologous chromosomes. Only two chromosomes are involved and the exchange is reciprocal and therefore balanced. Incidence of 1:600 newborns. Autosomal reciprocal translocations are usually spontaneous (occur at time of conception) and do not come from parents.

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"Cytogenically Balanced" Reciprocal Translocation

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When examined by karyotype, individual with this type of translocation seems to have the correct amount of gentic material. If parent is uneffected, it is assumed that child will be as well. If the child has a "de novo" translocation (did not get it from parents), it is not known what the breakpoints of the translocation were or what genes might have been effected. Symptoms are unpredictable.

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Robertsonian Translocation

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Occurs with two acrocentric (very short p arm) chromosomes fuse together. Both lose their short arm and long arms fuse causing one chromosome. Involve only chromosomes 13, 14, 15, 21, 22. Incidence is 1:1000 in general community. Short arms usually have only multiple copies of ribosomal RNA genes and little other coding material. Their lose causes little/no phenotypic result. Since both long arms are intact, sort of like a balanced translocation and causes little/no phenotypic result.

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Deletion

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Abnormalities caused by loss of genetic material. Incidence is ~1/7000 newborns. There can be terminal or interstitial and are caused by either break and re-join, or improper crossing over. Can cause haploinsufficiency.

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Haploinsufficiency and Contiguous Gene Syndrome

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The inability of a single gene to carry out the function normally performed by two copies. Caused by deletion. Haploinsufficiency of multiple contiguous genes along a deleted section leads to Contiguous Gene Syndrome. Many large terminal deletions are a cause of mental retardation. Detected by FISH and array-CGH.

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1p-Syndrome

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Variable sized deletions of the 1p sub-telomeric region. Associated with mental retardation, dysmorphic features, and heart defects.

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Wolf-Hirschhorn Syndrome (4p)

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Variable sized deletions of the 4p sub-telomeric region. Associated with mental retardation and dysmorphic features.

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Cri du Chat Syndrome (5p)

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Variable sized deletions of the 5p sub-telomeric region. Present in ~1% of institutionalized mentally retarded pts. Associated with mental retardation, dysmorphic features, microcephaly, heart defects, and a "cat like cry" in infancy.

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Microdeletion Syndromes

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Size of deletions are similar in multiple pts. Often too small for conventional karyotyping techniques. The breakpoints are located in clusters of low-copy repeart (LCR) sequences. When recombination occurs between these misaligned regions, unequal crossover can occur resulting in deletion and duplication.

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DiGeorge/velocardiofacial syndrome (del 22q11.2)

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The most common microdeletion syndrome. Incidence of 1/2000-1/4000 newborns. Associated with developmental disability, heart defects, craniofacial dysmorphisms, palate defects, and parathyroid and thymic displasia.

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William's Syndrome (del 7q11.23)

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Microdeletion syndrome. Associated with facial dysmorphisms, supravalvular aortic stenosis, hypercalcemia, and a typical behavioral/cognitive profile (known as a "cocktail personality")

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Ring Chromosomes

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Abnormal marker chromosomes that form when a normal chromosome undergoes two breaks and the broken ends bind to produce a ring structure. Produce mitotic instability. Two sister chromatids become tangled in an attempt to disjoin at anaphase causing more breakage and fusion.

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Isochromosomes

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Have one arm missing and the other arm duplicated in a mirror image fashion. The result is monosomy for the missing arm and trisomy for the dulicated arm. Frequently seen in tumors.

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Prenatal Diagnosis

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Chromosomal analysis usually done on peripheral blood lymphocytes. Fetal cells obtained by amniocentesis or chorionic villus sampling (CVS).

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Amniocentesis

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Occurs during 15-20wk period of gestation. Amniotic fluid is sampled as it contains cells sloughed by the fetus. Advantage is that fluid can be tested for other diseases and neural tube disorders (spina bifida).

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Chorionic Villus Sampling (CVS)

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Can occur between 10-12 weeks of gestation. In this procedure, chroionic villi (extra-embryonic part of the blastocyst, the trophoblast) are sampled trans-cerviacally or trans-abdominally. Advantage is early diagnosis.

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Philadelphia Chromosome

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Example of one cancer related chromosome abnormality. Reciprocal translocation between chromosome 9 and 22. This translocation juxtaposes a proto-oncogene ABL from chromosome 9 (long arm) onto the BCR region of the long arm of chromosome 22. The result is abnormal cell growth. These cells have a selective growth advantage and are an important etiological factor in Chronic Myelogenous Leukemia (CML).

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Array-CGH Technique

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Patient DNA is isolated (usually from leukocytes) and labeled with fluorescent tags. Reference DNA is tagged with different color fluorescence. The samples are then co-hybridized to a slide that contains many DNA "probes" representing different genes within the genome. If normal, DNA will all show one uniform color (green). If there is a deletion or duplication, however, reference DNA will cause a color change (more red or more green).