Transcript No Slide Title

Robertsonian chromosome
translocations: the basics
a tutorial to show how
chromosomes which have been
rearranged as a result of a
Robertsonian 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 Robertsonian
(sometimes called centric fusion).
Reminder
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. Any of the pairs of chromosomes
can be involved. The chromosome number remains at 46. The
incidence of reciprocal translocations is about 1 in 500. There is
a separate tutorial about these.
Reminder
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. Any of the pairs of chromosomes
can be involved. The chromosome number remains at 46. The
incidence of reciprocal translocations is about 1 in 500. There is
a separate tutorial about these.
Compare this reciprocal exchange with a Robertsonian
translocation
which involves only the acrocentric chromosomes (chromosomes
13,14,15 and 21, 22), and results in the formation of a “new”
chromosome consisting of the whole of the long arms of the two
acrocentrics involved, which have been fused together.
The incidence of Robertsonian translocations in the general
population is about 1 in 1000.
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 (trisomic)
= 1.5 times normal amount
• One copy of genes (monosomic)
= 0.5 times normal amount
• Altered amounts may cause anomalies directly or may alter the
balance of genes acting in a pathway
Robertsonian* translocation
* named in honour of Dr WRB Robertson, an
American who first described the fusion of two
acrocentric chromosomes in his studies of insect
speciation in 1916.
Results from breakage of two acrocentric
chromosomes (numbers 13, 14, 15, 21, 22) at or
close to their centromeres, with subsequent
fusion of their long arms to form one
chromosome.
An acrocentric chromosome has
its centromere close to one end.
The normal acrocentric chromosomes
The short arms of each chromosome
are lost but this is of no clinical
importance (as they contain genes
for ribosomal RNA for which there are
multiple copies on the other
acrocentric chromosomes).
The fact that the DNA structure on
the short arms of the acrocentrics is
so similar may be an important
component in the formation of an
individual family’s Robertsonian
translocation.
The total chromosome number is
reduced to 45 as two of the
acrocentrics have fused to form one
(new) chromosome.
Depending on where the breakage occurs, the
resultant translocation chromosome can have
one or two centromeres, but this has no
functional effect.
As no gain or loss of important genetic material occurs,
Robertsonian translocation carriers are normal. Once
translocation chromosomes have been formed, they can be passed
on to offspring.
The commonest Robertsonian translocation is fusion
between one chromosome 13 and one chromosome 14.
A carrier for a Robertsonian
(13;14) translocation
Karyotype for a male carrier is
descibed as:
45,XY,der(13;14)(q10;q10)
Although Robertsonian translocation carriers are
asymptomatic, they can produce unbalanced
gametes which can result in monosomic or trisomic
zygotes.
Translocation trisomy 13 (Patau syndrome):
three copies of chromosome 13
For instance, segregation of the
chromosomes of a carrier of a
Robertsonian 13;14 translocation
can result in children with
translocation trisomy 13 being born
as shown here.
Although children with translocation Patau syndrome (trisomic
for genes on chromosome 13) may be born alive, they usually
die in the first few weeks or months of life. Trisomy 14 is
lethal, as is trisomy for chromosomes 15 and 22 during early
fetal life.
Although der(13;14)(q10;q10) is the most frequent
Robertsonian translocation, the most important clinical
effect of Robertsonian translocations arises from those
involving chromosome 21 as they can result in the birth of
children with translocation Down syndrome (trisomic for the
genes on chromosome 21).
In fact, second in frequency and clinically the
most important Robertsonian translocation is
der(14;21).
Robertsonian translocations involving
chromosome 22 are rare.
The clinical features of Down syndrome caused by either
regular trisomy 21 or by a Robertsonian translcoation
involving chromosome 21 are exactly the same because
both result in three copies of the genes on chromosome
21.
The recurrence risks for a family differ depending on
whether the Down syndrome is caused by trisomy 21 or an
unbalanced Robertsonian translocation.
The pedigree which follows shows the
typical pedigree features associated with a
Robertsonian translocation.
What are they?
Age 42
Died at birth:
heart disease
and blockage of
bowel
Age 42
Age 20
Down
syndrome
Miscarriage at
4 weeks
Down
syndrome
Mother young
age (22 yrs)
when child with
Down
syndrome born
Age 42
Died at birth:
heart disease
and blockage of
bowel
Age 42
Children with features of
Down syndrome in three
generations
Age 20
Down
syndrome
Miscarriage at
4 weeks
Miscarriage early in
pregnancy
Down
syndrome
The affected people in this family have translocation Down
syndrome.
The Robertsonian translocation is between
one chromosome 14 and
one chromosome 21
This partial karyotype of the affected people shows an
unbalanced karyotype:
two copies of chromosome 14
three copies of chromosome 21
This is the partial karyotype of the father of the son with Down
syndrome.
It shows a balanced Robertsonian translocation:
two copies of chromosome 14 and
two copies of chromosome 21
How the three
chromosomes of a
Robertsonian
translocation segregate at
meiosis
Usually two of them segregate together into one of
the gametes at meiosis whilst the remaining
chromosome segregates into another gamete.
This means there are three possible ways
in which the chromosomes will segregate,
as described next.
The two “normal” chromosomes and the Robertsonian
translocation chromosome in a carrier can segregate in three
ways - segregation pattern 1
Fertilisation with a normal gamete
Normal
gamete
The two “normal” chromosomes and the Robertsonian
translocation chromosome in a carrier can segregate in three
ways - segregation pattern 2
Fertilisation with a normal gamete
Normal
gamete
(Translocation
trisomy 14)
The two “normal” chromosomes and the Robertsonian
translocation chromosome in a carrier can segregate in three
ways - segregation pattern 3
Fertilisation with a normal gamete
Normal
gamete
(Translocation Down
syndrome)
The two “normal” chromosomes and the Robertsonian
translocation chromosome in a carrier can segregate in three
ways - the 3 segregation patterns
(Translocation
trisomy 14)
These three are lethal
(Translocation Down
syndrome)
As shown in the previous slide, of the possible segregants, monosomy
14, trisomy 14 and monosomy 21 are lethal.
The remaining possibilities are
• a child with normal chromosomes,
• a child with the balanced translocation, and
• a child with Down syndrome due to the unbalanced form of the
translocation.
A parent who is a
carrier for a
Robertsonian
translocation
involving
chromosome 21
(as shown here)
therefore has a high
theoretical risk after
conception of 1 in 3 of
having a child affected with
translocation Down
syndrome.
But ...
In clinical practice, the observed risk of having a liveborn child is less
than this.
For a female Robertsonian 14;21 carrier it is about 10%; for a male
Robertsonian 14;21 carrier it is about 1%. This is thought to be due to
loss through spontaneous miscarriage and perhaps effects of the
translocation on meiosis or selection of sperm carrying the
translocation.
Compare these figures with the low recurrence in regular trisomy 21
Down syndrome (ie three structurally separate copies of chromosome
21). Regular trisomy 21 is due to an error in cell division, and has a
recurrence risk of about 1 in 100.
This is why it is important to karyotype a person with Down syndrome
- to determine the chromosomal cause.
Most families with either reciprocal or Robertsonian
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.
An unbalanced karyotype is a recognised legal
indication for ending a pregnancy.
How does a Robertsonian translocation occur in the
first place?
Most Robertsonian 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.
About half the children with Down syndrome caused by an
unbalanced Robertsonian translocation have the condition as a
result of a de novo event.
Summary: Robertsonian translocation
• Results from breakage of two
acrocentric chromosomes (13, 14,
15, 21, 22) at or close to their
centromeres, with subsequent fusion
of their long arms to form one
chromosome.
• 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])