Principles+of+Clinical+Cytogenetics

=**Objectives**=


 * 1. Review the clinical indications for a chromosome analysis** (p.385-336)

__Prenatal__
 * Amniotic fluid or CVS analysis in mothers presenting with advanced maternal age (greater than 35 yrs), an ultrasound detected anomaly, abnormal quad marker screen, or parents with a history of genetic problems.
 * Couples with two or more fetal losses
 * Couples with infertility problems
 * Abortuses and malformed stillborns

__Postnatal__
 * To rule out classical chromosome syndromes
 * Individuals with unexplained mental retardation
 * Patients with multiple congenital anomalies
 * Siblings of a known carrier of a chromosome abnormality
 * Parents of a child with a chromosome abnormality
 * Individuals with ambiguous genitalia
 * Females iwth amenorrhea; pubertal failure in males and females

__Neoplasia__
 * Preleukemic conditions, leukemia, lymphoma, and solid tumors


 * 2. Categorize the severity of possible phenotypic outcomes as they related to the spectrum of genetic imbalances that can occur in chromosome abnormalities** (p.387)

The larger the genetic imbalance, the more devestating the result and the earlier the miscarriage.


 * Large genetic imbalance||Devestating of blastogenesis|| Transient implantation, implantation, or nonimplantation of conceptus||
 * ||Devestation of embryogenesis||Spontaneous 1st trimester miscarriage, miscarriage||
 * ||Major disruption of intrauterine morphogenesis||Stillbirth or early neonatal death to some extrauterine survival||
 * Smaller or no genetic imbalance||Moderate to mild distortion of intrauterine development||Substantial extrauterine survival; minimal or no discernible phenotypic effects||


 * 3. Review the concept of polyploidy, specifically triploidy, and differentiate the clinical manifestations observed when the extra haploid chromosome set is maternally or paternally inherited; describe how the concept of genetic imprinting relates to human development.** (p.388-390)

Polyploidy refers to changes in chromosome number where entire genome can be duplicated; in triploidy, there are three copies of every chromosome.

The parental origin of the extra set of haploid chromosomes results in different clinical maneifestations. When the extra set is paternal, the placenta is abnormally large with partially hydatidiform moles. When the extra set is maternal, the placenta is much smaller than the fetus and the fetus exhibits macrocephaly and fusion of fingers and toes. The maternal and paternal contributions to the development of hte embryo are not the same but both are necessary for normal development.

Genomic imprinting is set into the maternal and paternal gamates so that certain alleles are active in one parental gamate contribution, but not the other. Maternal contributions appear to be more important for the embryo while paternal contributions appear to be more important for development of the placenta and membranes.


 * 4. Describe the clinical significance of aneuploidy and the pathogenetic mechanisms underlying nondisjunction.** (p.390-392)

Aneuploidy occures in 3-4% of all clinically recognized pregnancies though most autosomal aneuploidies are incompatible with fetals survival and observes most frequently in miscarages.

Chromosomal trisomies have been reported in miscarriages for all chromosomes; Aneuploidy of gene rich chromosomes (1, 3, 6, 11, 12, 17, 19, and 22) result in a high genetic imbalance and is not compatible with survival while aneuploidy of gene poor chromsomes (8, 9 as mosaics and 13, 18, and 21) can be see in live births. Autosomal monosomies are extremely rare in both livebirths and recognized abortuses.

The most common cause of aneuploidy is chromosomal non-disjunction which can occur during meiosis I or meiosis II where chromosomes fail to segregate properly during meiotic divisions. If the extra chromosomes are heterozygous pairs, the trisomy originated from meiosis I non-disjunction; if the extra chromosomes are homologous pairs, the trisomy originated from meiosis II non-disjunction. An egg that has non-disjunction during meiosis II can still have a chance of producing normal gamates.


 * 5. Describe the clinical features of down syndrome, patau syndrome, and edwards syndrome.** (p.397-399)

__Down Syndrome__
 * Trisomy 21
 * Incidence: 1/700 births
 * Mental retardation
 * Epicanthic folds
 * Flat facial profile
 * Congenital heart defects
 * Intestinal stenosis
 * Umbilical hernia
 * Predisposition to leukemia
 * Hypotonia
 * Gap between first and second toe
 * Beta-amoloid is overproduced
 * Similar symptomes as Alzheimer's disease with myofibrillary tangles and dementia

__Patau Syndrome__
 * Trisomy 13
 * Incidence: 1/15,000 births
 * Microphthalmia
 * Polydactyly
 * Microcenphaly
 * Mental retardation
 * Cleft lip/palate
 * Cardiac defects
 * Umbelical hernia
 * Renal defects
 * Rocker-bottom feet

__Edward's Syndrome__
 * Trisomy 18
 * Incidence: 1/8,000 births
 * Prominent Occiput
 * Mental Retardation
 * Micrognathia
 * Low set ears
 * Short neck
 * Overlapping fingers
 * Congenital heart defects
 * Renal malformations
 * Limited hip abduction
 * Rocker bottom feet


 * 6. Describe the concept of aberrant chromosome segregation of both a parental balanced reciprocal translocation and robertsonian translocation and their related clinical outcomes** (p.405-407)

Abbrent chromosomal rearrangements can break chromosmes and reattach incorrectly. Balanced reciprocal translocations are when two chromosomes break and are recipocally reattached but no genetic material is lost; this results in the individual being phenotypically normal. If this individual should have a child, there would be no problem if he should pass on two normal chromosomes. If he passes on two abnormal chromosomes, the child will also be normal phenotypically but be a carrier. However, if he passes on one normal and one abnormal chromosome, there is not a complete set of genetic information and a partial trisomy will result.

Robersonian translocations are the fusion of acrocentric chromosomes. The short arms of acrocentric chromosomes usually code for the same thing (rRNA genes) so the loss of genetic information can be tolerated.


 * 7. Review the features of segmental aneusomy syndromes and discribe how fluorescence in situ hybridization (FISH) is used in the clinical cytogenetics laboratory to confirm the diagnosis of these genetic disorders.** (p.408,413)

Segmental aneusomal syndromes commonly have duplications or deletions of small chromosomal segments containing few genes that are functionally related, but by chance are closely linked on the crhomsome. Phenotype tends to be variable because of different possible break points and the occurence is usualyl sporadic but may cluster in families.

The pathogenic mechanism responsible for microdeletion and microduplication syndromes involves unequal crossing over between misaligned siter chromatids or homologous chromsomes containing homologous copies of a repeated DNA sequence.

FISH is a physical DNA mapping technique in qhich a DNA proble labeled with a marker molecule is hybridized to chromosomes on a slide an visualized using UV light. This technique can be used to detect submicroscopic deletions, additonal chromosomal material, and cryptic translocations. FISH can also be ued to identify marker chromomosomes, and detect minimal residual disease in neoplasia, prenatal aneuploidy, and subtelomeric rearrangements in idiopatic mental retardation.


 * 8. Describe the principles of X-inactivation and the clinical consequences associated with skewed X-inactivation.** (p.414, 415)

In somatic cells of females, only one X chromosome is active transcriptionally to allow for dosage compensation. The second chromosome is condensed and inactive in interphase nuclei and is called a barr body. Inactivation occures in the blastocyst stage and is random for paternal and maternal X-chromosomes and is permenent in somatic tissues

X-inactivation is initiated at the X-inactivation center on Xq13. XIST gene is only expressed from the inactive X and inactivation occurs through DNA methylation. Muatations in the XIST gene can lead to abnormal phenotype.

65% if genes are completely inactivated; 15% of genes completely escape inactivation and are epxressed; 20% of genes are inactivated in some cells and activated in others. More Xp genes escape inactivations than Xq and may partly explain why Xp deletions are more severe than Xq deletions.

5-10% of normal females demonstrate extreme skewing of inactivation pattern. For x-linked disorders, unfortunate Lyonization may produce expression of a disease phenotype. Skewed X-inactivation occures in both balanced and unbalanced X and autosomal translocations.


 * 9. Review the clincal features of Klinefelter and Turner syndromes.** (p.416, 417)

__Klinefelter Syndrome__
 * 47, XXY
 * Incidence: 1/1,000 newborn males
 * Normal face (gee thanks...thats //so// helpful)
 * Tendency towards long arms and legs
 * Small genitalia
 * Abnormal breast development (gynecomastia)
 * IQ usually normal but IQ of some less than 80
 * Infertility

__Turner Syndrome__
 * 45, X
 * Short stature
 * Low posterior hairline
 * Webbing of neck
 * Coactation of aorta
 * Broad chest and widely spaced nipples
 * Cubitus valgus
 * Streak ovaries
 * Infertility
 * Amenorrhea
 * Pigmented nevi
 * Peripheral lymphedema at birth


 * 10. Describe sex chromosome abnormalities that can result in sex reversal phenotypes.**