Chromosomes II Dr Pupak Derakhshandeh, PhD Ass Prof Medical Science of Tehran University Email: derakhshandeh@tums.ac.ir Website: http://medicine.tums.ac.ir/en/Professor_cv.aspx?lt=8&uid=5984 (English) http://medicine.tums.ac.ir/fa/Professor_cv.aspx?lt=8&uid=889 (Persian)

Trisomy 18, 47 Ch.

Trisomy 18, 47 Ch. incidence of about 1 in 3,000 There is a 3:1 preponderance of females to males Thirty percent of affected newborns die within the first month 50% by two months and 90% by one year. severe mental retardation microcephaly overlapping fingers, and rocker bottom feet Neurologically they are hypertonic Other common malformations include congenital heart, kidney, .... abnormalities.

Trisomy 18, 47 Ch.

Trisomy 13 (XX/XY, 47 Ch) has an incidence of 1 in 5,000 Forty-four percent of affected newborns succumb in the first month of life and 69% by six months Only 18% of the babies born with trisomy 13 survive the first year microcephaly microophthalmia (small eyes) cleft lip or cleft palate polydactyly (extra fingers) congenital heart defects urogenital defects brain malformations severe mental retardation.

Turner Syndrome ( 45, X) 45, X

Turner Syndrome (45, X)

Turner syndrome Only females One X chromosome Or has two X chromosomes but one is damaged Short stature Delayed growth of the skeleton Sometimes heart abnormalities Usually infertile due to ovarian failure Diagnosis is by blood test (karyotype) 1 out of every 2,500 female live births worldwide Short neck with a webbed appearance

Kleinefelter/47XXY

Klinefelter syndrome (47, XXY) In boys and men 47 chromosomes with XXY sex chromosomes XXY is one of the most common chromosomal abnormalities 1 in 500 male births the most common genetic cause of male infertility Often : undiagnosed : variation in clinical presentation Small testes , insufficient production of testosterone , and infertility

Klinefelter syndrome (47, XXY) Breast enlargement, lack of facial and body hair, a rounded body type , to be overweight , and be taller than their fathers and brothers Learning and/or behavioral problems Testosterone replacement corrects the symptoms of androgen deficiency

Kleinefelter XXY

Fragile X Syndrome 1 in 3,600 males and 1 in 4,000 to 6,000 females with the full mutation worldwide It is estimated that 1 in 250 females and 1 in 700 males are carriers of the premutation. It is second only to Down Syndrome as a cause of mental retardation Fragile X syndrome appears in children of all ethnic, racial and socio-economic backgrounds

Fragile X Syndrome most common inherited form of familial mental retardation (CGG)n trinucleotide expansion in the FMR1 gene leading to the typical Martin-Bell phenotype Clinical features vary depending on age and seX Expansion of a (CCG)n repeat in the FMR2 gene corresponds to the FRAXE fragile site which lies distal to FRAXA and is also associated with mental retardation, but it is less frequent and lacks a consistent phenotype

Fragile X Syndrome

Fragile X Syndrome

Chromosome abnormalities Abnormality of chromosome number or structure: Numerical Abnormalities Structural Abnormalities

Structural Abnormalities Deletions: A portion of the chromosome is missing or deleted (>5 Mb). Paraderwilli Syndrome (Ch 15) Angleman Syndrome (Ch 15) Imprinting effect

Deletion refers to the loss of a segment of a chromosome DELETIONS Deletion refers to the loss of a segment of a chromosome This can be terminal (close to the end of the chromosome on the long arm or the short arm) or it can be interstitial (within) eg.DGS II

DELETIONS

Structural Abnormalities Duplications: A portion of the chromosome is duplicated, resulting in extra genetic material. Oncogenes (c-onc, c-fos, c-myc)

DUPLICATIONS refers to an extra chromosomal segment within the same homologous chromosome or an extra chromosomal segment on another nonhomologous chromosome. Again, the clinical findings are highly variable depending upon the chromosomal segments involved. Gene expantion: in Huntington Disease/ Fragile X, ….

Structural Abnormalities Translocations: When a portion of one chromosome is transferred to another chromosome.

There are two main types of translocations. In a reciprocal translocation, segments from two different chromosomes have been exchanged. In a Robertsonian translocation, an entire chromosome has attached to another at the centromere.

Reciprocal TRANSLOCATIONS Translocation involves two nonhomologous chromosomes (e.g., chromosome 2 and chromosome 6) Following a break in each of the chromosomes, and subsequent reunion a segment of chromosome 2 becomes attached to chromosome 6

TRANSLOCATIONS

Balanced reciprocal translocation

Structural Abnormalities Inversions: A portion of the chromosome has broken off, turned upside down and reattached, therefore the genetic material is inverted. eg Ch9 inv in Iran

involve only one chromosome Inversions involve only one chromosome the intervening segment is rejoined in an inverted or opposite manner. Since there is no loss nor gain of chromosomal material, inversion carriers are normal Paracentric: does not include the centromere pericentric:inverted segment contains the centromere In meiosis, the normal chromosome and the inverted chromosome will form a loop to allow pairing of specific DNA sequences that occur within the inversion loop result in gametes with both deletions and duplications inversion carriers have a relatively low risk of having abnormal offspring.

Inversions

Meiosis in an individual heterozygous for a pericentric inversion

Rings: A portion of a chromosome has broken off and formed a circle or ring. This can happen with or without loss of genetic material.

Ring

Oncology Chronic Myelogenous Leukemia (CML) a clonal expansion of transformed hematopoietic progenitor cells: Myeloid Monocytic Erythroid Megakaryocytic lymphoid lineages

Molecular level CML: characterized by the bcr-abl fusion gene reciprocal translocation t(9;22)(q34;q11) creating the Philadelphia (Ph) chromosome survival time of patients : to 5 to 7 years

Hematology Bone marrow

Chronic myelogenous leukemia (CML) 15% to 20% of leukemias in adults incidence of 1 to 2 cases per 100,000 population

Chronic myelogenous leukemia occurs more frequently in males than in females (ratio of 1.3 to 1) Incidence: increases with age the median age at presentation is between 45 and 55 years which is an important consideration for the selection of therapeutic strategies stem-cell transplantation treatment with interferon-alfa (Intron A, Roferon-A)

The Philadelphia Chromosome a reciprocal translocation between the long arms of chromosome 9 and chromosome 22 the large segment of the c-abl gene from chromosome 9q34 to the part of the bcr gene on chromosome 22q11 in a head-to-tail fashion creating a hybrid bcr-abl gene that is transcribed into a chimeric bcr-abl mRNA

Detection of bcr-abl Cytogenetic analysis Ph chromosome in 90% of patients with CML Such analysis is tedious and time-consuming allows the examination of only 20 to 25 metaphases per bone marrow sample misses the 5% of patients who are Ph-negative but bcr-abl-positive Despite these shortcomings, cytogenetic analysis is the gold standard in the diagnosis of CML.

FISH Fluorescence in situ hybridization allows for the analysis of metaphase Results of FISH studies are easily quantifiable

fluorescence in situ hybridization (FISH)

fluorescence in situ hybridization (FISH)

FISH Bcr Abl Abl-Bcr

Abl-Bcr