Transcript Types of chromosome abnormalities

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.