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).

ReminderA 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.

ReminderA 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

• A chromosome is made of

DNA (and histones)

• Each chromosome contains its own set of genes in a linear order

• There are two copies of each autosomal gene: one on each homologue

FZD2AKAP10ITGB4KRTHA8WD1SOST

MPP3

MLLT6

STAT3

BRCA1GFAPNRXN4NSF

NGFR

CACNB1HOXB9HTLVRABCA5CDC6ITGB3

Chromosome 17

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.

The normal acrocentric chromosomes

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 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.

The commonest Robertsonian translocation is fusion between one chromosome 13 and one chromosome 14.

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.

A carrier for a Robertsonian (13;14) translocationKaryotype for a male carrier is descibed as: 45,XY,der(13;14)(q10;q10)

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 Robertsonian translocation carriers are asymptomatic, they can produce unbalanced gametes which can result in monosomic or trisomic zygotes.

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.

Translocation trisomy 13 (Patau syndrome): three copies of chromosome 13

In fact, second in frequency and clinically the most important Robertsonian translocation is der(14;21).

Robertsonian translocations involving chromosome 22 are rare.

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).

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 Age 42Died at birth: heart diseaseand blockage of bowel

Age 20

Miscarriage at4 weeks

Down syndrome

Down syndrome

Age 42 Age 42Died at birth: heart diseaseand blockage of bowel

Age 20

Miscarriage at4 weeks

Down syndrome

Down syndrome

Children with features of Down syndrome in three generations

Mother young age (22 yrs) when child with Down syndrome born

Miscarriage early in pregnancy

The Robertsonian translocation is between one chromosome 14 and one chromosome 21

The affected people in this family have translocation Down syndrome.

This partial karyotype of the affected people shows an unbalanced karyotype:

two copies of chromosome 14three 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

Normal gamete

Fertilisation with a 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 gameteNormal gamete

(Translocationtrisomy 14)

The two “normal” chromosomes and the Robertsonian translocation chromosome in a carrier can segregate in three ways - segregation pattern 3

Normal gamete

Fertilisation with a 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

These three are lethal

(Translocation Down syndrome)(Translocation

trisomy 14)

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.

therefore has a high theoretical risk after conception of 1 in 3 of having a child affected with translocation Down syndrome.

A parent who is a carrier for a

Robertsonian translocation

involving chromosome 21 (as shown here)

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. (p.a.farndon@bham.ac.uk)