Download Unbalanced Translocation Breakout

Unbalanced Translocation
Breakout
Kent Nicholls
5p- Society
Rebecca Okashah
Genetic Counselor
Children's Hospital of San Antonio
July 26, 2014
San Antonio, TX
5p- Society Annual Conference
Revised 8/3/2014
Balanced & Unbalanced Translocations
Defined
• Balanced Translocation
• A chromosome abnormality caused by pieces of separate
chromosomes breaking off of their original chromosomes and
switching places. All of the genetic material is present
(balanced).
• Unbalanced Translocation
• When an unbalanced translocation occurs, there is both too
much of one chromosome and too little of another chromosome
present as a result of pieces of separate chromosomes breaking
off of their original chromosomes and switching places.
• In 5p-, the translocation involves the short arm (p) of
chromosome 5 and any chromosome.
What causes an unbalanced translocation?
• One parent has a balanced translocation
• New occurrence at conception (meiosis)
Diagram of a translocation (reciprocal)
Possible Results
• For example, if there is a parent with a balanced
translocation involving 5p and 10q having a child, the
possible results are:
a) Normal
b) Translocation carrier – child has a balanced translocation
c) 5p- and 10q+
Partial monosomy of some portion of 5p and trisomy of some portion of 10q.
d) 5p+ and 10qTrisomy of some portion of 5p and partial monosomy of some portion of 10q.
• Mathematical risk is 25% for each possibility, but in
practice, the expected risk of carrying a child to term with
an unbalanced translocation (either c or d above) is
approximately 20%
How is an unbalanced translocation
detected?
• An unbalanced translocation is usually detected by a
blood test at birth or by an amniocentesis or CVS during
pregnancy.
Recurrence Risk for Future Children
• If a child has an unbalanced translocation and the
parents do not have a balanced translocation, then the
risk for future children is approximately 1%.
• If a child has an unbalanced translocation and one of the
parents has a balanced translocation, then the risk for
future children is approximately 20%.
• 70% of translocations are inherited
• the balanced translocation is equally likely to be from the mother
or the father
• the risk of a future child having an unbalanced translocation is
also affected by the size of the balanced translocation.
A person with an unbalanced translocation
is unique
• 5p- unbalanced translocations occur in about 10% of 5pcases
• Missing genetic material (5p deletion) and added genetic
material (partial duplication of another chromosome).
• The amount of protein synthesized is often proportional to the
number of gene copies present
• Extra genes can lead to excess protein and deletions can also
affect gene dosage
• Each child is unique with virtually infinite combinations of
missing and added material.
• 5p- is a spectrum disorder
• Classically defined Cri du Chat syndrome does not accurately
encompass the symptoms experienced by these children.
Prognosis for this group of children
• Our families are writing the book on this!
• Anecdotal observations suggest those persons with a
5p- unbalanced translocation may perform toward the
low end of the range of the 5p- spectrum.
• Insufficient information is available for persons with a
5p+ unbalanced translocation.
Options for having more children
• This is a very personal family decision and we respect
that!
• Adoption
• Prenatal Testing
• Chorionic villus sampling (CVS) – at about 11 to 12
weeks
• Amniocentesis – at about 16 to 18 weeks of
pregnancy
• Non-Invasive Prenatal Testing (NIPT) analyzes cellfree fetal DNA circulating in maternal blood – at about
10 to 22 weeks
In Vitro Fertilization (IVF)
• Analyze, select and transfer only embryos that do not
have abnormalities in their chromosomes
• Comprehensive Chromosome Screening (CCS)
• Obtain 5-10 cells on day 5 or 6 from blastocyst
• Examine cells with quantitative real-time polymerase chain reaction
(qPCR)
• Preimplantation Genetic Diagnosis (PGD) of embryos
prior to transferring to the uterus
• A single blastomere is removed on day 3
• Genetic evaluation is performed using PCR, FISH, or comparative
genomic hybridization (CGH).
• Process, limitations, issues, successes
Personal Stories
• SB – personal experience with IVF
• LD – personal experience with IVF
• Other stories from break-out attendees
Research Suggestions
• What can be done to mitigate symptoms and enhance
quality of life?
Q&A with Rebecca Okashah
• Can an unbalanced translocation be missed on test
and leave other family member at risk?
• Can an unbalanced translocation be mosaic?
• Why is my child not similar to another child with the
same chromosome unbalanced translocation (i.e. 5 &
10)
• Are some unbalanced translocations less impactful,
such as 5 & x?
• What is about 5p+ children?
• What if our family has multiple people with 5p- but no
translocation is identified?
Internet links for more information
• Comprehensive Chromosome Screening (CCS)
•
•
•
•
http://www.medscape.com/viewarticle/817499
http://www.rmact.com/getting-started/fertility-testing/ccs-comprehensivechromosome-screening
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0061838
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3348286/
• Preimplantation Genetic Diagnosis (PGD)
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•
•
http://emedicine.medscape.com/article/273415-overview
http://www.givf.com/geneticservices/whatispgd.shtml#chromosomerearrangemen
t
http://www.pennmedicine.org/fertility/patient/clinical-services/pgdpreimplantation-genetic-diagnosis/
• Non-Invasive Prenatal Testing (NIPT)
•
•
http://www.rcog.org.uk/files/rcog-corp/SIP_15_04032014.pdf
http://www.ncbi.nlm.nih.gov/pubmed/24785862