Rare inherited coagulation and fibrinolytic defects that challenge diagnostic laboratories

What Are Translocations? What Disorders Do They Cause? - WebMD

Translocations, in genetics, happen when chromosomes break and the pieces attach to other chromosomes. This mixing of genetic material has important results. The resultant chromosomes are lacking in some genetic information and have excessive amounts of some. Many important clinical conditions like Down syndrome and chronic myelogenous leukemia result from translocation mutations. 

A change in chromosome structure and content caused by translocation is a translocation mutation. Many genes may be transferred between chromosomes. Such translocation mutations can cause disorders of growth, development, and function of the body's cells and systems.

Human cell nuclei have 23 pairs of chromosomes. Twenty-two of them are paired (called autosomes) and numbered 1 to 22. The last pair is the sex chromosomes (X and Y). Each chromosome has two arms, named p and q. These two arms are joined at a structure called the centromere.

A translocation chromosome mutation can be of two types — reciprocal and Robertsonian. In a reciprocal translocation, two different chromosomes have exchanged pieces with each other. In a Robertsonian translocation, an entire chromosome attaches to another at the centromere.

As long as no genetic material is gained or lost in the cell, translocations are called balanced translocations. When genetic material is lost or increased, it is an unbalanced translocation.

Changes in chromosome structure affect many genes and disrupt protein synthesis of the cell. Disturbance of protein synthesis can affect the structure and function of cells and tissues. Apart from translocations, the changes in chromosome structure are:

Deletions. This happens when a chromosome breaks and part of its genetic material is lost. Deletions can be small or large and can involve from a few to hundreds of genes. An example of deletion is the 22q11.2 deletion syndrome, which causes defects of the heart, mouth, throat, brain, kidneys, and other organs of affected children. 

Duplications. This happens when there is abnormal copying of part or whole of the genetic material of a chromosome. The cell then has extra copies of genetic material from the copied segment. 

Inversions. This happens when a chromosome breaks in two places. The broken piece turns around and attaches to the chromosome. Some genetic information may be lost. Inversions may involve the centromere.

Isochromosomes. These chromosomes have two identical arms. Instead of the usual one p and one q arm, isochromosomes have two p or two q arms. They're lacking in genetic material from the missing arm and have twice the material from the extra arm. 

Dicentric chromosomes. These chromosomes have two centromeres. They result from the fusion of two chromosome pieces that each have a centromere. Dicentric chromosomes are unstable and often have lost some genetic material.

Ring chromosomes. These are formed when the ends of a chromosome break off. The arms then join to form a circular structure. Some genetic material is lost, and the centromere may or may not be present in the ring. 

The human body has millions of cells. Changes in chromosome structure in any individual cell are probably of no importance. That one cell won't function well and might die soon. Translocations are important when they occur in a large population of cells.

Translocation mutations are most harmful when they occur in a sperm, ovum, or zygote. At that time, there is only one copy of each chromosome. Any loss or addition of genetic material to a chromosome can be catastrophic. The one cell multiplies into millions of cells, forming the tissues and organs of a human. The translocation and its changes in genetic information will affect each cell. Sometimes, the translocation happens later, after conception. There will be two populations of cells, one with normal chromosomes and one with the translocation. This is known as mosaicism.

Translocation mutations can be unimportant to the person who has them. For example, a person may have a balanced translocation between chromosomes 7 and 21. The q arms of each chromosome have been switched. But this person has all the genetic material required for normal protein synthesis and function. They have no health problems at all because the chromosome translocation is balanced.

Sperm and ova are formed for reproduction, and each pair of chromosomes is split up. The sperm and ova have only one copy of each chromosome. These reproductive cells might have a chromosome 7 with the 21q attached. This sperm or ova also has a normal chromosome 21. When it combines with the opposite reproductive cell to form a zygote, there will be three 21q in the cell. The baby will be born with three copies of the q arm of chromosome 21 and will have the manifestations of trisomy 21 (Down syndrome). 

Down syndrome. This is usually caused by chromosomal non-disjunction. The sperm or ova has two full chromosomes 21, and the zygote ends up with three (trisomy 21). But a small proportion of cases are caused by chromosomal translocation, most often between chromosomes 14 and 21. The child has two full chromosomes 21, and a 21q attached to chromosome 14. The q arm of chromosome 21 appears to carry the genetic material that causes the Down syndrome manifestations. These children have serious anomalies of the heart, intestines, and spine. Later, these children have hypothyroidism, diabetes, vision and hearing issues, and variable intellectual disability.

Chronic myelogenous leukemia (CML). This blood cancer is associated with a chromosomal translocation between chromosomes 9 and 22. A part of chromosome 9 attaches to chromosome 22. The changed chromosome 22 is called the Philadelphia chromosome. This chromosome disorder causes the formation of tyrosine kinase, which helps cancer cells to grow. The Philadelphia chromosome is also sometimes found in acute lymphocytic leukemia.

Lymphoma and acute myeloid leukemia (AML). Chromosomal translocation between chromosomes 8 and 11 can cause myeloproliferative disorders, which lead to acute myeloid leukemia. It also causes lymphoma.

Some facts about chromosomal translocations:

Chromosomal translocations can be catastrophic or harmless. If you have a balanced translocation, you can be healthy throughout life. Problems only happen with reproduction.

Chromosomal translocations may be inherited from parents or arise anew around the time of conception.

There is no cure for chromosomal translocations. They're usually present in each cell of your body and will remain for life.

Translocations are not infectious. You can have social interactions and sexual contact without fear. You can also donate blood. 

New Test Can Detect Both Genetic And Chromosomal ... - ScienceDaily

One-step screening for both genetic and chromosomal abnormalities has come a stage closer as scientists announced that an embryo test they have been developing has successfully screened cells taken from spare embryos that were known to have cystic fibrosis.

They told a news briefing at the 25th annual meeting of the European Society of Human Reproduction and Embryology in Amsterdam June 30 that, as a result, they would be able to offer clinical trials to couples seeking fertility treatment later this year.

The researchers based in the USA and the UK have been able to prove that the technique, known as genome-wide karyomapping, was capable of not only detecting diseases caused by a specific gene mutation, in this case cystic fibrosis, but that it was also capable of detecting aneuploidy (an abnormal number of any of the 23 pairs of chromosome) at the same time. This is the first time they have been able to demonstrate that the test can work in cells taken from embryos that have already been diagnosed with the cystic fibrosis gene mutation using conventional preimplantation genetic diagnosis (PGD).

Gary Harton, PGD scientific director of the Genetics & IVF Institute in Fairfax, Virginia (USA) told a news briefing: "Karyomapping is a universal method for analysing the inheritance of genetic defects in the preimplantation embryo without any prior patient or disease specific test development, which often delays patient treatment. For the first time, the inheritance of both single gene defects and chromosomal abnormalities can be detected simultaneously at the single cell level. Unlike other methods, this is achieved entirely by analysing the DNA sequence at over 300,000 locations genome-wide in parents and appropriate family members, often children already affected by a disease, and comparing their sequence with that inherited by the embryo. This can be achieved very rapidly using current microchip technology known as microarray."

With karyomapping it is not necessary to know the exact DNA mutation that is being sought; the scientists just need to take the relevant chunk of DNA from the parent that carries the mutation somewhere along its length, and if it matches a chunk of DNA from the embryo, then they know the embryo has inherited the mutation. As karyomapping involves analysing chromosomes, it also detects the existence of aneuploidy at the same time.

"The range of applications is broad and includes single gene defects, abnormal chromosome number, structural chromosome abnormalities and HLA [human leukocyte antigen] matching in 'saviour sibling' cases," said Mr Harton.

Karyomapping was developed by Professor Alan Handyside of the London Bridge Fertility Gynaecology and Genetics Centre in London (UK), and Mr Harton has been providing samples and DNA information in order to test the method and validate it for use in the clinic.

"The hope is that clinicians will be able to test embryos for specific genetic diseases and know that, with one test, they are transferring chromosomally normal embryos. This will be a step forward from current technology that is mostly limited to choosing one test or the other," explained Prof Handyside.

Karyomapping would also be quicker and cheaper. Currently, developing a PGD test for a single gene defect can take weeks or months, as scientists have to identify the exact patient or disease-specific genetic mutation first before screening for it, which is labour-intensive and costly. By contrast, karyomapping can be carried out without such extended pre-test development; at present, it takes about three days, but Mr Harton and his colleagues believe this could be reduced to 18-24 hours.

In this most recent stage of their research they examined cells from five embryos that had been donated for medical research by a couple who had received successful fertility treatment, including PGD for cystic fibrosis. The embryos had developed to the blastocyst stage, which is about five days after fertilisation. Conventional PGD had already identified which embryos were unaffected, affected or were carriers of the disease. Karyomapping of cells from the donated embryos confirmed these diagnoses, but, in addition, it was able to identify which parent carried the affected chunk of DNA. Karyomapping also revealed two aneuploidies in two embryos, which had not been detected by the earlier PGD.

Mr Harton said: "This demonstrates that karyomapping, following genome-wide analysis of a single cell biopsied from embryos at the blastocyst stage, can provide highly accurate analysis for cystic fibrosis, combined with the detection of chromosomal aneuploidy. Now that vitrification [an improved method of embryo freezing] has improved embryo survival after thawing, it should be possible to vitrify embryos at the blastocyst stage, either before or after biopsy, and analyse the embryos for virtually any genetic disease and screen for aneuploidy of all 23 pairs of chromosomes simultaneously. This approach could make PGD by karyomapping less expensive than conventional single disease PGD because fewer embryos will be biopsied, more embryos will be chromosomally normal following growth to the blastocyst stage, and there is no need to custom develop tests for each disease or couple interested in PGD."

Prof Handyside concluded: "These tests have helped us to learn everything we can before we start to treat actual patients. I am confident that we will be offering a clinical trial to patients using karyomapping some time this year."

New Chromosomal Abnormality Identified In Leukemia Associated With Down ...

Researchers identified a new chromosomal abnormality in acute lymphoblastic leukemia (ALL) that appears to work in concert with another mutation to give rise to cancer. This latest anomaly is particularly common in children with Down syndrome.

The findings have already resulted in new diagnostic tests and potential tools for tracking a patient's response to treatment. The research, led by scientists from St. Jude Children's Research Hospital, also highlights a new potential ALL treatment. Clinicians are already planning trials of an experimental medication targeting one of the altered genes.

This study is published in the October 18 online edition of Nature Genetics.

"A substantial proportion of children with ALL lack one of the previously identified, common chromosomal abnormalities. Also, children with Down syndrome have an increased risk of ALL, but the reasons why are unclear," said Charles Mullighan, M.D., Ph.D., assistant member in the St. Jude Department of Pathology. Mullighan is senior author of the study, which involved scientists from 10 institutions in the U.S. And Italy. "Our results have provided important data regarding the mechanisms contributing to leukemia in these cases," he said.

Instead of the normal pairs of 23 chromosomes, individuals with Down syndrome inherit an extra copy of one chromosome, in this case chromosome 21. Chromosomes are made of DNA and carry the genes that serve as the assembly and operations manual for life. Down syndrome is associated with a variety of medical and developmental problems, including a 10- to 20-fold increased risk of ALL. But patients with Down syndrome rarely have the genetic and chromosomal alterations commonly associated with childhood ALL. Until recently the genetic basis of the elevated risk for these patients was unknown.

The new gene alteration was identified by St. Jude scientists following up on an earlier observation. They had previously found a recurring deletion in a region of DNA duplicated on the X and Y chromosomes. The region is known as pseudoautosomal region 1 or PAR1.

The PAR1 deletion was found only in patients with a subtype of ALL known as B-progenitor ALL. It was most common in children with both B-progenitor ALL and Down syndrome. In this study, investigators screened almost 400 children with ALL, including 75 patients with Down syndrome. The deletion was present in 7 percent of patients with B-progenitor ALL, but in more than half of the patients with both B progenitor and Down syndrome.

The deletion results in a fusion of two genes, P2RY8 and CRLF2. The fusion puts CRLF2 expression under the control of the P2RY8 promoter. As a result, CRLF2 expression jumps as much as 10 fold.

"CRLF2 over-expression identifies a group of ALL cases which were not previously well characterized, and suggests some novel treatment approaches that may improve patient survival. Patients with Down syndrome are particularly vulnerable to complications from standard chemotherapy, and could therefore benefit from novel therapies," said Karen Rabin, M.D., of Texas Children's Cancer Center and a study co-author. She is a Baylor College of Medicine assistant professor of pediatric hematology/oncology.

The CRLF2 protein normally forms part of a receptor where a small growth factor known as a cytokine binds to white blood cells known as lymphocytes. Both the cytokine, thymic stromal lymphopoietin (TSLP), and CRLF2 are known to play important roles in the development of immune cells known as T lymphocytes as well as in inflammation and allergic disease. They had not previously been linked to leukemia.

CRFL2 is the second gene implicated in development of B-progenitor ALL in patients with Down syndrome. The first, a gene called JAK2, was identified in 2008. JAK2 belongs to a family of genes that produce enzymes called kinases. If permanently switched on, kinases can trigger the uncontrolled cell growth that is a hallmark of cancer.

JAK mutations have also been linked to other cancers. Drugs targeting JAK kinases are already in clinical trials against a variety of blood disorders in adults. Additional trials are being planned against other subtypes of childhood ALL.

In this study, researchers reported a significant association between alterations in both the CRFL2 and JAK2 genes. Almost all JAK mutations were observed in patients with CRLF2 alterations. Almost 28 percent of children with Down syndrome and ALL had changes in both the CRFL2 and JAK genes.

"It has been a mystery as to why the JAK mutations in Down syndrome ALL are different from those seen in other cancers," Mullighan said. "Here we show that the JAK mutations in ALL are almost always observed together with a chromosomal alteration that results in over- expression of CRLF2."

When both the JAK mutation and increased CRLF2 production were introduced into white blood cells growing in the laboratory, those cells were transformed and no longer needed cytokines to grow. Neither genetic alteration on its own produced the same effect. Researchers also reported their impact could be weakened by the addition of drugs that target JAK mutations.

"We showed that the two proteins, CRLF2 and mutant JAK2, physically interact, and together transform white blood cells. This work has identified a new pathway contributing to the development of leukemia," Mullighan said. A next step is to determine if these mutations also interact in mouse models of ALL.

Other authors of this paper include J. Racquel Collins-Underwood, Letha A.A. Phillips, Wei Liu, Jing Ma, Elaine Coustan-Smith, Richard T. Williams, Jinjun Cheng, Ching-Hon Pui, Susana Raimondi and James Downing, all of St. Jude; Michael L. Loudin of Baylor; Jinghui Zhang of the National Cancer Institute (NCI); Richard Harvey and Cheryl Willman, of the University of New Mexico; Fady Mikhail and Andrew Carroll, of the University of Alabama at Birmingham; Nyla Heerema of Ohio State University; Giuseppe Basso, of the University of Padua, Padua, Italy; and Andrea Pession of the University of Bologna, Bologna, Italy.

The work was supported in part by National Cancer Institute, the Bear Necessities Pediatric Research Foundation, the Children's Cancer Research Foundation, the National Institutes of Health and ALSAC.

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