Chromosomal Abnormalites Flashcards
Karyotyping
. Involves light microscopic examination of stained chromosomes from metaphase cells
. Assesses: gender, ploidy, large-scale structural disorders
Indications for performing karyotyping
. Patients w/ features of known chromosomal disorder
. Pt w/ unexplained intellectual disability
. Stillborn infant w/ malformations
. Couple w/ 2+ unexplained pregnancy losses
. Pt w/ tumor assoc. w/ chromosomal abnormalities
Fluorescence in situ hybridization (FISH)
. Fluorescence microscopic examination of chromosomes from interphase or metaphase cells following hybridization w/ fluorescent labeled DNA probes
Polyploidy
. Fertilized egg contains either 69 (3n, triploidy) or 92 (4n, tetraploidy) instead of 46 (2n) chromosomes
. Triploid and tetraploid conceptions are relative common, but non-viable and most spontaneously abort
Autosomal aneuploidy
. Trisomy most common in 13, 16, 18, 21, and 22
. All but trisomy 21 are lethal and cause of 50% of spontaneous abortions
. Only 25% of people w/ trisomy 21 survive to term
. Monosomy (loss os 1 chromosome) is lethal other than Turner syndrome
. Patau syndrome(1/1000 births) and Edwards syndrome(1/6000 births) are less common than downs, assoc. w/ multiple congenital malformations, survival beyond 1 yr is rare
Down syndrome
. Characteristic facial appearance, palmar creased dec. mm. Tone, intellectual disability, congenital heart defects, hearing loss, and early Alzheimer’s disease
. Partial/complete trisomy of chromosome 21 (95% complete trisomy)
. Caused from non-disjunction during gametogenesis
. Association w/ mother are and risk for having downs child
. Other causes: robertsonian translocation (3-4%), mosaicism (1-2%)
Molecular basis for Down syndrome
. Presence of extra chromosome 21 results in overexpression of its genes
. No single gene has been fully linked to any feature assoc. w/ downs
. SOD1: overexpression may cause H2O2 accumulation
. COL64A1: overexpression causes heart defects
. ETS2: overexpression may cause hypotonia
. DYRK: overexpression cause intellectual disability
. APP: overexpression may cause early Alzheimer’s
Screening for Down syndrome
. Screening assesses maternal age-based risk, ultrasound, and maternal serum testing
. Prenatal diagnosis requires cytogenetic analysis of cells via amniocentesis, chorionic villus sampling, or percutaneous umbilical blood sampling
Robertsonian translocation
. One pair of chromosome 14 and 21 combine to form 14q21q
Mosaicism
. Some cells have normal karyotype
. Others have trisomic karyotype
. Depending on bother extent of mosaicism and the type of cells affected
. Phenotype highly variable in clinical presentation
Sex chromosome aneuploidy
. Generally results in less severe clinical syndromes and are compatible w/ survival
. Klinefelter syndrome: 47, XXY, 1//1000 male births
. Turner syndrome: 45, X, 1/2500-1/5000 female births
. Trisomy X (47, XXX, 1/1000 female births)
Translocations
. Chromosome structural abnormalities in which genetic material is exchanged btw 2 different chromosomes
. Reciprocal translocations: genetic material in 2 non-homologous chromosomes is exchanges, can be causes of cancer)
. Robertsonian translocation: breakage of 2 acrocentric chromosomes (13, 14, 15, 21, 22) near centromeres w/ subsequent fusion of long arms, abnormal gametes may be produced
Inversions
. Result in occurrence of 2 breaks in chromosome when detached portion if reinserted but w/ reversed orientation
. Chromosomally abnormal gametes produced
Deletions
. Loss of genetic material will result if a chromosomal breakage goes unprepared
. Large-scale deletion syndromes include CRI-du-Chat syndrome and Wolf-Hirschhorn syndrome
. Microdeletions: prayer-willi and angelman
Duplications
. May result from unequal crossing over during meiosis or observed in offspring of individuals carrying balanced translocations or inversions
