DiGeorge Syndrome 22q(del) Individuals with the DiGeorge syndrome often have cardiac defects, immune system deficiencies and can be moderately retarded. • The cause of the DiGeorge syndrome is a defect in chromosome 22, where one of the bands in the long arm has been deleted. • The deletion can be suspected by looking at the karyotype and can be confirmed by FISH.
karyotype • This image shows the karytype of an individual with the DiGeorge syndrome. By looking carefully at the pair of 22's, you can see that there is a light band missing in the chromosome to the right. It might be easier to see the defect in the composite karyotype of chromosome 22 from the same individual.
Fragile X Syndrome • A condition characterized genotypically by mutation of the distal end of the long arm of the X chromosome (at gene loci FRAXA or FRAXE) and phenotypically by cognitive impairment, hyperactivity, SEIZURES, language delay, and enlargement of the ears, head, and testes. MENTAL RETARDATION occurs in nearly all males and roughly 50% of females with the full mutation of FRAXA.
enlargement of the ears, head, and testes. MENTAL RETARDATION occurs in nearly all males and roughly 50% of females
Unusual Inheritance Patterens Due to Genomic Imprinting Genomic imprinting: the differential expression of alleles depending on the parent of origin. Two microdeletion syndromes, Prader-Willi syndrome and Angelman syndrome, are of particular importance because they illustrate the newly recognized phenomenon of genomic imprinting .
Each disorder has a distinct phenotype. PWS, a neurobehavioral disorder affecting 1 in 10,000 newborns, has dysmorphic features that vary throughout childhood, adolescence and adulthood. These include hypotonia and poor sucking reflex, hyperphagia leading to obesity, short stature and extremities, and moderate mental retardation.
In contrast, AS features include hyperactivity, laughter outbursts, clumsy, jerky movements, large facial features, and severe mental retardation.
Both result from either a maternal or paternal deletion on chromosome 15 or from uniparental disomy, inheritence of both chromosomes of a pair from one parent. The expression of these syndromes is determined by parental origin of genes on chromosome 15. 70% of all patients have the deletion(15q11-q13). Only paternal deletions occur in PWS and only maternal deletions in AS. Uniparental disomy occurs when both chromosomes of a pair are inherited from one parent. In PWS two copies of chromosome 15 are inherited from the mother, whereas, in AS two copies are inherited from the father.
These observations suggest that certain autosomal genes might be differentially expressed depending on whether they were inherited from the father or from the mother. Maternal and paternal genetic contributions of autosomal genes are not necessarily equivalent, and the genetic contributions from both parents are necessary for normal development.
Changes in chromosome structure can take various forms: • Translocations e.g. balanced reciprocal translocation 46,XY,t(5;10)(p13;q25) • Deletions e.g. Short arm deletion of 5, cri du chat syndrome 46,XY,del(5)(p25) • Ring chromosomes e.g. 46,XY,r(3)(p26q29) • Duplications e.g. partial duplication 46XX,dup(2) (p13p22) • Inversions e.g. pericentric inversion 46,XY,inv (11) (p15q14) • Isochromosomes e.g. 46,X,I(Xq) • Centric fragments e.g. centric fusion translocation 45,XX,t(13;14)(p11;q11)
chromosomal disorder Down syndrome
autosomal abnormalities
trisomy 13
Numerial abnormalities
trisomy 18 Cri du chat syndrome
Structural abnormalities DiGeorge syndrome
Sex chromosome abnormalities Structural abnormalities
Numerial abnormalities
FRAX PWS,AS(imprinting) Turner syndrome Klinefelter Syndrome gonadal dysgenesis
Diagnosis ---karyotype analysis
FISH
Sample: blood cell,
Individual after birth
amniotic fluid, chorionic villus
Fetus (Prenatal detection )
Treatment---No way
Methods of making karyotype 1. Peripheral blood lymphocytes are separated off from venous blood and added to nutrient medium which stimulates T lymphocytes to divide. 2. The cells are cultured at 37oC for about 3 days and then colchicine added to arrest cell division during metaphase. 3. Hypotonic saline is then added which causes the cells to swell and release the chromosomes which are then fixed, mounted on a slide and stained for analysis. 4. Several different staining methods are used to enable identification of individual chromosomes e.g. 5. G (Giemsa), Q (Quinacrine), R (Reverse) and C (Centomeric heterochromatin) banding.
Fluorescence In Situ Hybridization (FISH) Probes can be hybridized to the DNA contained within chromosomes immobilized on microscope slides. Athis technique is called in situ hybrizization because the DNA in metaphase chromosomes fixed on slides is denatured in place to expose the two strands of DNA, thus allowing a labeled probe to hybridize to the chromosomal DNA. The most common method of labeling probes for in situ hybridization to chromosomes is with a flurescent dye.
Multicolor (24-color) FISH (mFISH): Metaphase chromosomes from normal human fibroblasts after multicolor FISH (mFISH). a) True or merged color profile from different fluorochromes used. b) Computer generated pseudocolor image of the same metaphase spread. Note each chromosome is painted in a different color.