* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Types of chromosome abnormalities
Copy-number variation wikipedia , lookup
Biology and sexual orientation wikipedia , lookup
Point mutation wikipedia , lookup
Hybrid (biology) wikipedia , lookup
Medical genetics wikipedia , lookup
Comparative genomic hybridization wikipedia , lookup
Designer baby wikipedia , lookup
Genomic imprinting wikipedia , lookup
Microevolution wikipedia , lookup
Segmental Duplication on the Human Y Chromosome wikipedia , lookup
Epigenetics of human development wikipedia , lookup
Artificial gene synthesis wikipedia , lookup
Polycomb Group Proteins and Cancer wikipedia , lookup
Gene expression programming wikipedia , lookup
Saethre–Chotzen syndrome wikipedia , lookup
DiGeorge syndrome wikipedia , lookup
Down syndrome wikipedia , lookup
Genome (book) wikipedia , lookup
Skewed X-inactivation wikipedia , lookup
Y chromosome wikipedia , lookup
Structural Chromosomal Abnormalities Mohamad Nusier M.D., Ph.D. Structural chromosomal abnormalities – – – – – – – Translocations Insertions Inversions Deletions Ring formation Isochromosomes Extra Supernumerary Accessory Chromosome Structural chromosomal abnormalities...cont • • • • Translocations – 2 different chromosomes break and rejoin incorrectly Inversions – 2 breaks in the same chromosome Insertions – Piece of chromosomes inserted Deletions – Piece of chromosome missing Chromosomal Structural Changes - Normal ----> - Duplication ----> ABCDEFG ABCBCDEFG - Deletion ----> AB_DEFG - Insertion ----> ABCXDEFG - Inversion ----> ACBDEFG - Translocation ----> AGFBCDE Origins of chromosomal rearrangements Types of Rearrangements In Term of consequences • Balanced: abnormalities do not change gene dosage (The number of copies of a given gene present in a cell or nucleus. An increase in gene dosage can result in the formation of higher levels of gene product) – Inversions. – Translocations. • Imbalanced: abnormalities alter gene dosage causing aneuploidy (the presence of an abnormal number of chromosomes in a cell) – Deletions. – Duplications. Translocations • Transfer of DNA segments from one chromosome to another. – Reciprocal: • Arise when two chromosomes break and exchange pieces; two new derivative chromosomes will form. • Involves any chromosome – Robertsonian: • Break points are at or close to centromeres of two acrocentric chromosomes • Chromosomes 13, 14, 15, 21, 22 Reciprocal Translocations • Incidence in population is 1 in 500 • The most common type • Break in any chromosome at any point • Occur at meiosis • Phenotypically normal • Usually needs FISH to be identified. • *der: derivative Reciprocal Translocation at Meiosis • Normally chromosomes pair to form bivalents. • Reciprocal translocation heterozygote form a cluster known as pachytene quadrivalent (cross-shape). – Homologous materials align. • Segregation in several different ways. Segregation of Reciprocal Translocations • Independent homologous segregation during meiosis I can result in one of two types of segregation • Alternate segregation = Alternate chromosomes go to each gamete resulting in balanced gametes • Adjacent segregation = Adjacent chromosomes go to each gamete resulting in duplicated and deficient gametes Robertsonian translocations • Often 14:21 joined • Lose satellite • Reduce chromosome number by 1, but no loss • Phenotypically normal – problems at meiosis • Involved in evolution Genome restructuring by translocations (Robertsonian) • Short arrows indicate breakpoints in one homolog of each of two pairs of acrocentric chromosomes. The resulting fusion of the breaks yields one short and one long metacentric chromosome. • Under appropriate conditions, the short metacentric chromosome may be lost. Thus, we see a conversion from two acrocentric pairs of chromosomes into one pair of metacentrics. Formation of a 14q21q Robertsonian translocation in Down syndrome. Cause in less than 5% of cases. Formation of a 14q21q Robertsonian translocation in Down syndrome. Cause in less than 5% of cases. Inversions • Reversal of segment of chromosome • If too small cannot detect by karyotype • Very rare in humans • Paracentric – within one chromosome arm • Pericentric - reversed segment includes centromere • Pericentric - includes centromere • Paracentric - not involving centromere Insertions • Segment of one chromosome inserted into another Duplication Possible pairing configurations in heterozygotes of a standard chromosome and a side-by-side duplication. Duplicated segments may be (a) in tandem or (b) in reverse order. Deletions • Terminal - loss of end of chromosome – 46,XY,del(10)(q26) missing long arm of 10 • Interstitial – loss of segment from within chromosome – 46,XY,del(10)(q24q26) missing segment of 10 • All result in unbalanced karyotype • Partial monosomy • Serious clinical effect Isochromosome • • • • • Two copies of the same arm Mirror image around centromere Centromeres part in wrong plane Two groups: Replaces a normal chromosome – Results in monosomy for 1 chromosome – Arm and trisomy for the other arm Ring Chromosome Extra Supernumerary Accessory Chromosome • • • • • Abnormal chromosome in addition to 46 Small and difficult to identify Sometimes called marker chromosomes Difficult to work out effect on person May be benign or cause serious mental handicap Standard nomenclature for chromosome karyotypes 46,XY: normal male chromosome constitution 47,XX,+21: female with trisomy 21, Down’s syndrome 47,XY, +21[10]/46,XY[10]: Male who is a mosaic of trisomy 21 cells and normal cells (10 cells scored for each karyotype) 46,XY,del(4)(p14): Male with distal deletion of the short arm of chromosome 4 band designated 14 46,XX,dup(5)(p14p15.3): female with a duplication of the short arm of chromosome 5 from bands p14 to p15.3 Standard nomenclature for chromosome karyotypes 45,XY,der(13;14)(q10;q10): A male with a balanced Roberstonian translocation of chromosomes 13 and 14. Karyotype shows that one normal 13 and one normal 14 are missing and replaced with a derivative chromosome 46,XY,t(11;22)(q23;q22): A male with a balanced reciprocal translocation between chromosome 11 and 22. The breakpoints are at 11q23 and 22q22 46,XX,inv(3)(p21;q13): An inversion on chromosome 3 that extends from p21 to q13; because it includes the centromere, this is a pericentric inversion 46,X,r(X): A female with one normal X chromosome and one ring X chromosome 46,X,i(Xq): A female with one normal X chromosome and an isochromosome of the long arm of the X chromosome Examples of Microdeletion Syndromes • • • • Wolf-Hirschhorn Syndrome Cri Du Chat Syndrome William’s Syndrome Miller-Dieker Syndrome Del(4p) Del(5p) Del(7)(q11.2) Del(17)(p13.1-13.3) • Prader-Willi/Angelman syndrome Del(15)(q11-13) • DiGeorge Syndrome Del(22)(q11) • WAGR syndrome Del(11)(p13) Del(4p)(Wolf-Hirschhorn Syndrome) WHS Karyotype: Del(4p) Del(5p) (Cri Du Chat Syndrome) • Incidence: 1/50,000 live births • A distinct, shrill, cat-like cry (secondary to hypoplastic larynx), Mental retardation • 5-10% (parental translocation) Del(5p) (Cri Du Chat Syndrome) Williams Syndrome Miller-Dieker Syndrome Deletions found consistently in several different types of solid tumors in humans. Band numbers indicate recurrent breakpoints. Philadelphia chromosome • The Philadelphia chromosome was first observed in 1960 and is found in 95% of cases of chronic myeloid leukaemias. • The Philadelphia chromosome is a reciprocal translocation of DNA between the long arms of chromosomes 22 and 9 - t(9;22). • The portion of 9q translocated contains abl, a protooncogene that is the cellular homolog of a tyrosine kinase coded by the Abelson murine leukaemia virus - ABL. Translocations found consistently in several different types of solid tumors in humans. Band numbers indicate breakpoints. Chromosome aberrations associated with representative solid tumors. • Meningioma: del(22)(q11)1 • Neuroblastoma: del(1)(p36), del(11)(q23) • Renal cell carcinoma: del(3)(p14.2–p25) or translocation of this region • Retinoblastoma, osteosarcoma: del(13)(q14.1) or translocation of this region • Small-cell lung carcinoma: del(3)(p14–p23) • Wilms' tumor: del(11)(p15) The Pseudoautosomal Regions • Genes located within them (so far only 29 have been found) are inherited as autosomal genes. • Males have two copies of these genes: one in the pseudoautosomal region of their Y, the other in the corresponding portion of their X chromosome. SRY • A gene located on the short (p) arm just outside the pseudoautosomal region. • It is the master switch that triggers the events that converts the embryo into a male. • Without this gene, you get a female instead. It appears, then, the femaleness is the "default" program. 46,XY female with deletion of SRY gene • During meiosis, the pseudoautosomal regions on the short arms of X and Y pair and undergo recombination • The SRY gene is located next to the Yp pseudoautosomal region, and if it is transferred to the X chromosome, a 46,XX male or 46,XY female would result Indications for cytogenetic analysis • Patients of any age who are grossly retarded physically or mentally, especially if there are associated anomalies. • Any patient with ambiguous internal or external genitalia or suspected hermaphroditism. • Girls with primary amenorrhea and boys with delayed pubertal development. Up to 25% of patients with primary amenorrhea have a chromosomal abnormality. • Males with learning or behavioral disorders who are taller than expected (based on parental height). • Certain malignant and premalignant diseases. Indications for cytogenetic analysis...cont • Parents of a patient with chromosome translocation. • Parents of a patient with a suspected chromosomal syndrome if there is a family history of similarly affected children. • Couples with a history of multiple spontaneous abortions of unknown cause. • Couples who are infertile after more common obstetric and urologic causes have been excluded. • Prenatal diagnosis.