Transcript No Slide Title

Reciprocal chromosome
translocations: the basics
a tutorial to show how
chromosomes which have been
rearranged as a result of a
reciprocal translocation can
segregate, and the clinical
consequences
Professor P Farndon,
Clinical Genetics Unit, Birmingham
Women’s Hospital
13.11.06
Chromosomal Translocations
A translocation is formed when there has been transfer of material
between chromosomes, requiring breakage of both chromosomes,
with repair in an abnormal arrangement.
If the exchange results in no loss or gain of DNA (ie genes), the
individual is clinically normal and is said to have a balanced
translocation.
A balanced translocation carrier is, however, at risk of producing
chromosomally unbalanced gametes.
There are two types of translocation: reciprocal and centric fusion
(Robertsonian)
A reciprocal translocation usually involves breakage of two
non-homologous chromosomes (ie one chromosome from
each of two different pairs) with exchange of the
fragments.
All chromosomes can take part in reciprocal
translocations, which are usually unique to a particular
family.
The incidence of reciprocal translocations in the general
population is about 1 in 500.
A separate tutorial considers Robertsonian translocations.
Reminder: chromosomes, genes and
heredity
FZD2
AKAP10
ITGB4
KRTHA8
WD1
SOST
• A chromosome is made of
DNA (and histones)
MPP3
MLLT6
STAT3
BRCA1
GFAP
NRXN4
NSF
• Each chromosome
contains its own set of
genes in a linear order
• There are two copies of
each autosomal gene: one
on each homologue
NGFR
Chromosome 17
CACNB1
HOXB9
HTLVR
ABCA5
CDC6
ITGB3
How do the unbalanced forms of a
translocation cause clinical problems?
• By altering the amounts of products of the genes involved
• Three copies of genes (partial trisomy for a particular
chromosome arm)
= 1.5 times normal amount
• One copy of genes (partial monosomy for a particular
chromosome arm due to deletion of this area)
= 0.5 times normal amount
• Altered amounts may cause anomalies directly or may alter the
balance of genes acting in a pathway
The pedigree which follows shows the
typical pedigree features associated with a
reciprocal translocation. What are they?
Alfred
Hutchinson
1.3.1916
Nancy
Charles
Green
76 yrs
17.6.1919
Marion
73 yrs
10 weeks
Henry
Davis
66 yrs
Margaret
George
Hutchinson
7.2.46
63 yrs
Mary
19.2.1948
11 weeks
John
Clarke
2.2.1958
Christine
29.10.61
Philip
Davis
3.9.1963
10 weeks
James
Jane
Emma
22.4.1950 17.6.1953
Infertile
Died in infancy
Congenital anomalies
10 weeks
Clare
Michael
6.5.1875
15.2.1970
Robert
Anna
24.4.1974
1.2.1977
Stillborn
Congenital anomalies
10 weeks
William
Smith
12.9.76
9 weeks
Peter
Jane
Jordan
Amy
George
11.11.1989
12.5.1993
7.6.1998
Congenital anomalies
3.3.1997
17.6.1999
Multiple miscarriages
Alfred
Hutchinson
1.3.1916
Nancy
Charles
Green
76 yrs
17.6.1919
Marion
73 yrs
10 weeks
Henry
Davis
66 yrs
Margaret
George
Hutchinson
7.2.46
63 yrs
Mary
19.2.1948
11 weeks
John
Clarke
2.2.1958
Christine
29.10.61
Philip
Davis
3.9.1963
10 weeks
James
Jane
Emma
22.4.1950 17.6.1953
Infertile
Died in infancy
Congenital anomalies
10 weeks
Clare
Michael
6.5.1875
15.2.1970
Robert
Anna
24.4.1974
1.2.1977
Stillborn
Congenital anomalies
10 weeks
William
Smith
12.9.76
9 weeks
Peter
Jane
Jordan
Amy
George
11.11.1989
12.5.1993
7.6.1998
Congenital anomalies
3.3.1997
17.6.1999
Three children with congenital abnormalities
in three generations
Reciprocal translocation
Testing Clare Davis showed that she was a carrier of a
balanced reciprocal chromosome translocation
between the short arm of one chromosome number 7
and the long arm of one chromosome number 13.
Reciprocal translocation
The parts of the
chromosome arms
distal to the breaks
have exchanged
places,
resulting in a
chromosome 7 missing
part of its short arm but
containing part of the
long arm of
chromosome 13.
In a reciprocal translocation, the total
chromosome number remains at 46.
The chromosome 13 involved
in the translocation has lost
part of its long arm which now
contains part of the short arm
of chromosome 7.
In the example which follows, we are using a different
translocation - to stress that for reciprocal translocations
the breakpoints are different from family to family..
The translocation is between the long arm of one
chromosome number 2 (grey) and the short arm of
one chromosome number 11 (pink)
Balanced reciprocal
translocation carrier
Two of these four chromosomes
are usually passed into individual
gametes at meiosis.
The four chromosomes can be
passed on (segregate) in several
different combinations.
Balanced reciprocal
translocation carrier
Gametes
Gamete with
normal
chromosomes
Zygote
For example, the
normal chromosome 2
and the normal
chromosome 11 can
segregate into a
gamete
When fertilised by a normal gamete, the
resultant zygote will have a normal karyotype,
and cannot pass the translocation on to future
generations.
Balanced reciprocal
translocation carrier
The translocated
chromosome 2
Gametes
and the
translocated
chromosome 11
can segregate
into a gamete
Zygote
Gamete with
normal
chromosomes
When fertilised by a normal
gamete, the
resultant zygote will have the
correct number of genes from
chromosomes 2 and 11, and will
be a translocation carrier.
Note that as there has been no gain nor loss of chromosomal
material, this is a called a “balanced rearrangement”, and the
person who has this pattern is a “translocation carrier”.
Being a balanced reciprocal translocation carrier will have no
effects on the health of this person.
He or she, of course, can pass on various combinations of
the normal and translocated chromosomes to children.
Balanced reciprocal
translocation carrier
Gametes
Zygote
The normal chromosome 2 and
the translocated chromosome 11
can segregate into a gamete
When fertilised by a normal
gamete, the zygote will have three
copies of genes from the long arm
of chromosome 2 and only one
copy of genes from the short arm
of chromosome 11. This is trisomy
for part of chromosome 2 and
monosomy for part of chromosome
11.
Gamete with
normal
chromosomes
Balanced reciprocal
translocation carrier
Gametes
The translocated chromosome 2
and the normal chromosome 11
can segregate into a gamete
Gamete with
normal
chromosomes
Zygote
When fertilised by a normal gamete,
the zygote will have only one copy of
genes from the long arm of
chromosome 2 and three copies of
genes from the short arm of
chromosome 11. This is monosomy
for part of chromosome 2 and
trisomy for part of chromosome 11.
A carrier of a balanced reciprocal translocation can
therefore produce unbalanced gametes, resulting in
zygotes with partial trisomy and/or partial monosomy for
the defined chromosomal regions.
This chromosome imbalance may result in abortion,
stillbirth, malformation and/or mental retardation.
The precise effects will depend on the particular genes in
the areas involved in the translocation.
Summary of outcomes
Normal no risk to
children
Normal - but
risk to
children of
having
unbalanced
translocation
Balanced reciprocal
translocation carrier
Miscarriage,
congenital
malformation,
developmental
delay, mental
abnormality
Miscarriage,
congenital
malformation,
developmental
delay, mental
abnormality
The relative frequency of each possible gamete is not readily predicted,
because the size and position of the chromosome segments involved in
the translocation may have an effect on the pairing of the chromosomes
at meiosis, perhaps making some segregant patterns (including some
unbalanced segregants not shown here) more likely in the gametes
than others.
The risk of having a liveborn child with each of the possible outcomes
therefore depends on its frequency in the gametes and on the
likelihood of the conceptus with that abnormality developing to term.
These depend on the effects of the genes on the translocated
segments and the amount of chromosome imbalance.
Most families with reciprocal translocations undertake
fetal karyotyping (by chorionic villus sampling at about
10 weeks or amniocentesis at 16 weeks in pregnancy)
to confirm that the baby has either the normal pattern of
chromosomes, or the balanced form.
How does a reciprocal translocation occur in the first
place?
The majority of reciprocal translocation carriers have inherited the
balanced translocation chromosomes from a parent.
Occasionally, however, the parents have normal karyotypes. The
translocation in the offspring must have arisen de novo during the
meiosis which produced the egg or sperm which formed the person
with the translocation.
Reciprocal translocations probably occur because of mispairing of
non-homologous chromosomes at meiosis, with subsequent transfer
of material from one non-homologous chromosome to another.
Once the translocation chromosomes have been formed they can be
passed on to offspring, and future generations.
7
13
To form this reciprocal
translocation between
the short arm of one
chromosome number 7
and the long arm of one
chromosome number 13
breaks must have
occurred in each arm
during one meiosis in an
ancestor, probably due to
mispairing
Summary: Reciprocal chromosome translocation
• Exchange of chromosomal
material between two
chromosomes
• Individual clinically normal if
no gain or loss of material
(translocation carrier)
• Unbalanced products may
cause chromosomally
abnormal baby, miscarriage,
stillbirth, infertility
• Other family members should
be offered testing for carrier
status
The end!
• Thank you for completing this revision aid
• We are interested in your comments about this
aid. Please email Professor Farndon.
([email protected])
© P Farndon 2003