Researchers at King’s College London and King’s College Hospital, part of King’s Health Partners Academic Health Sciences Centre, have developed a new, non-invasive blood test that can reliably detect whether or not an unborn baby has Down’s syndrome. The test can be given earlier in pregnancy and is more accurate than current checks.
Down’s syndrome, also referred to as trisomy 21, is a genetic disorder caused by the presence of all or part of an extra copy of chromosome 21 in a person’s DNA. Current screening for Down’s syndrome and other trisomy conditions includes a combined test done between the 11th and 13th weeks of pregnancy, which involves an ultrasound screen and a hormonal analysis of the pregnant woman’s blood. Methods such as chorionic villus sampling (CVS), which involves taking cell samples from the placenta, and amniocentesis (using a sample of amniotic fluid), are also used to detect abnormalities but they are both invasive and carry a risk of miscarriage.
Several studies have shown that non-invasive prenatal diagnosis for trisomy syndromes using foetal cell free (cf) DNA from a pregnant woman’s blood is highly sensitive and specific, making it a potentially reliable alternative that can be done earlier in pregnancy.
Kypros Nicolaides, Professor of Fetal Medicine at King’s College London and Head of the Harris Birthright Research Centre for Fetal Medicine at King’s College Hospital, and colleagues have now demonstrated the feasibility of routine screening for trisomies 21, 18, and 13 by cfDNA testing. Testing done in 1005 pregnancies at 10 weeks had a lower false positive rate and higher sensitivity for foetal trisomy than the combined test done at 12 weeks. Both cfDNA and combined testing detected all trisomies, but the estimated false-positive rates were 0.1 percent and 3.4 percent, respectively.
‘This study has shown that the main advantage of cfDNA testing, compared with the combined test, is the substantial reduction in false positive rate. Another major advantage of cfDNA testing is the reporting of results as very high or very low risk, which makes it easier for parents to decide in favour of or against invasive testing,’ said Professor Nicolaides.
A second Ultrasound in Obstetrics & Gynecology study by the group, which included pregnancies undergoing screening at three UK hospitals between March 2006 and May 2012, found that effective first-trimester screening for Down’s syndrome could be achieved by cfDNA testing contingent on the results of the combined test done at 11 to 13 weeks. The strategy detected 98 percent of cases, and invasive testing was needed for confirmation in less than 0.5 percent of cases.
The authors conclude that screening for trisomy 21 by cfDNA testing contingent on the results of an expanded combined test would retain the advantages of the current method of screening, but with a simultaneous major increase in detection rate and decrease in the rate of invasive testing. Kings College London

Problems with a key group of enzymes called topoisomerases can have profound effects on the genetic machinery behind brain development and potentially lead to autism spectrum disorder (ASD), according to research. Scientists at the University of North Carolina School of Medicine have described a finding that represents a significant advance in the hunt for environmental factors behind autism and lends new insights into the disorder’s genetic causes.

‘Our study shows the magnitude of what can happen if topoisomerases are impaired,’ said senior study author Mark Zylka, PhD, associate professor in the Neuroscience Center and the Department of Cell Biology and Physiology at UNC. ‘Inhibiting these enzymes has the potential to profoundly affect neurodevelopment — perhaps even more so than having a mutation in any one of the genes that have been linked to autism.’

The study could have important implications for ASD detection and prevention.

‘This could point to an environmental component to autism,’ said Zylka. ‘A temporary exposure to a topoisomerase inhibitor in utero has the potential to have a long-lasting effect on the brain, by affecting critical periods of brain development. ‘

This study could also explain why some people with mutations in topoisomerases develop autism and other neurodevelopmental disorders.

Topiosomerases are enzymes found in all human cells. Their main function is to untangle DNA when it becomes overwound, a common occurrence that can interfere with key biological processes.

Most of the known topoisomerase-inhibiting chemicals are used as chemotherapy drugs. Zylka said his team is searching for other compounds that have similar effects in nerve cells. ‘If there are additional compounds like this in the environment, then it becomes important to identify them,’ said Zylka. ‘That’s really motivating us to move quickly to identify other drugs or environmental compounds that have similar effects — so that pregnant women can avoid being exposed to these compounds.’

Zylka and his colleagues stumbled upon the discovery quite by accident while studying topotecan, a topoisomerase-inhibiting drug that is used in chemotherapy. Investigating the drug’s effects in mouse and human-derived nerve cells, they noticed that the drug tended to interfere with the proper functioning of genes that were exceptionally long — composed of many DNA base pairs. The group then made the serendipitous connection that many autism-linked genes are extremely long.

‘That’s when we had the ‘Eureka moment,’’ said Zylka. ‘We realised that a lot of the genes that were suppressed were incredibly long autism genes.’

Of the more than 300 genes that are linked to autism, nearly 50 were suppressed by topotecan. Suppressing that many genes across the board — even to a small extent — means a person who is exposed to a topoisomerase inhibitor during brain development could experience neurological effects equivalent to those seen in a person who gets ASD because of a single faulty gene.

The study’s findings could also help lead to a unified theory of how autism-linked genes work. About 20 percent of such genes are connected to synapses — the connections between brain cells. Another 20 percent are related to gene transcription — the process of translating genetic information into biological functions. Zylka said this study bridges those two groups, because it shows that having problems transcribing long synapse genes could impair a person’s ability to construct synapses.

‘Our discovery has the potential to unite these two classes of genes — synaptic genes and transcriptional regulators,’ said Zylka. ‘It could ultimately explain the biological mechanisms behind a large number of autism cases.’ University of North Carolina School of Medicine

Beckman Coulter, Inc., and IRIS Diagnostics announce the launch of the Alifax automated Erythrocyte Sedimentation Rate (ESR) analysis system through a distribution agreement with Alifax.

The automated ESR analysis systems are designed to fit all workloads, including small hospitals, large reference laboratories, core laboratories and satellite locations. The automated ESR system delivers increased productivity, efficiencies in laboratory labour utilization and reduced turnaround times (TAT), along with improved patient outcomes and physician satisfaction.

“This patented technology is a breakthrough in turnaround time – generating subsequent results every 35 seconds or less, versus one hour for standard ESR analysis by the reference Westergren method,” said John Blackwood, senior vice president, Product Management, Beckman Coulter Diagnostics. “The small sample volume and STAT capability are expected to reduce ER waiting times and significantly minimize the need for patient specimen redraws.”

Employing patented technology, the Alifax ESR system provides fully automated, hands-off operation in a small footprint and processes the same whole blood tubes from the hematology analyser.

ESR is a common blood test, and is a non-specific measure of inflammation. Standard ESR analysis is a measure of red cells settling over time, typically one hour, and variations occur in the results, depending on the degree of specimen viscosity and presence of inflammatory proteins. Alifax’s technology measures the kinetics of red blood cell aggregation by capillary photometry and reads aggregation over a ten second period.

Down syndrome, more commonly known as ‘trisomy 21′ is very often accompanied by pathologies found in the general population: Alzheimer’s disease, leukaemia, or cardiac deficiency. In a study conducted by Professor Stylianos Antonarakis’ group from the Faculty of Medicine of the University of Geneva (UNIGE), researchers have identified the genomic variations associated with trisomy 21, determining the risk of congenital heart disease in people with Down syndrome. The targeted and specific study of chromosome 21 revealed two genomic variations, which, in combination, are the hallmark of hereditary cardiac deficiency.
Heart disease is a common disorder of Down syndrome. While the presence of a third gene in the n°21 pair (which characterises the disease) increases the risk of heart disease, it is not the sole cause: genetic variations—or polymorphisms—as well as certain environmental factors also contribute to it. Genetic variations create the diversity of human beings, their predispositions, and the differences in the expression of similar genes.
As part of a study carried out on the risk of congenital heart disease in people with Down syndrome, the geneticists led by Stylianos Antonarakis who conducts the research at UNIGE’s Department of Genetic and Developmental Medicine observed the dominating role of two types of polymorphisms: the nucleotide and the variability in the number of copies of a gene (CNV, which stands for copy number variation).
To verify these observations, the scientists created a tailor-made chromosome 21; their analyses revealed two areas of variability in the number of copies of a gene (or CNV), and one area identified by a nucleotide polymorphism (or SNP), which can be associated with the risk of heart deficiency. Therefore, this study highlights the role of two CNVs and one SNP in the cardiac pathogenesis of people with Down syndrome for the first time, revealing the genetic complexity of a common symptom of trisomy 21.
For the geneticist-authors of this study, the genetic architecture of the risk of congenital heart disease in individuals with Down syndrome must henceforth be understood as a complex combination, revealing the 21st chromosome, nucleotide polymorphism, and variability in the number of copies of a gene all at once; three factors to which we must add to the rest of the genome a still unidentified genetic variation, which Professor Antonarakis’ group is already tracking.
…and also the risk of chronic myeloid leukemia
In parallel, this same group has made progress in understanding another relatively common symptom of Down syndrome, by tracking the genetic variations that identify chronic myeloid leukemia in the body’s cells. EurekAlert

Researchers have discovered the first inherited gene mutation linked exclusively to acute lymphoblastic leukemia (ALL) occurring in multiple relatives in individual families. The discovery of the PAX5 gene mutation was led by St. Jude Children’s Research Hospital and others.
The mutation was identified in two unrelated families in which pediatric ALL has been diagnosed in multiple generations. The mutation involved a single change in the DNA sequence of PAX5, a gene that is known to be deleted, mutated or rearranged in some B cell tumours, including ALL. This is the first time changes in PAX5 have been linked to an inherited cancer risk.
‘Pioneering work from St. Jude and others has identified inherited variations in other genes that modestly increase the risk of developing ALL, but few had been identified in familial leukaemia,’ said co-corresponding author Charles Mullighan, MBBS(Hons), MSc, M.D., an associate member of the St. Jude Department of Pathology. ‘Prior studies had identified inherited mutations in families with multiple types of cancer including leukaemia, but not in families with ALL alone.’
While inherited mutations have been linked to an increased risk of breast, colon and other cancers, particularly adult cancers, very few have been tied to childhood tumours. ALL affects about 3,000 children nationwide annually, making it the most common childhood tumour.
‘For families with several generations of cancer patients, it means a lot to know that scientists and clinicians are working together to better understand the genetic factors that explain their family’s increased risk,’ said co-author John T. Sandlund, a member of the St. Jude Department of Oncology. ‘They are hopeful that other families, as well as their own, might benefit from this research.’
The mutation was found in the normal cells and leukaemia cells of eight ALL patients from several generations of two unrelated families. The work was led by researchers at St. Jude, Memorial Sloan-Kettering Cancer Center in New York and the University of Washington, Seattle.
The newly identified mutation is a single letter change in the DNA sequence of PAX5. The change results in the amino acid glycine being substituted for serine at amino acid 183 in the PAX5 protein. While PAX5 sequence mutations are common in sporadic cases of ALL, this mutation is the first identified at this location in the protein.
The mutation was discovered by sequencing the exome of normal cells from seven ALL patients in the two families and the exomes of the leukemic cells of four of these patients. The exomes from three relatives unaffected by leukaemia were also sequenced.
Researchers reported that the leukaemia cells all carried a single copy of PAX5 that included the mutation. The patients had all lost the normal version of the gene due to the partial deletion of chromosome 9, where PAX5 is located. The loss resulted in a marked reduction of normal PAX5 activity in the leukaemia cells. In contrast, family members who carried the mutant gene, but who had not developed leukaemia, retained the normal copy of the gene.
Researchers studied 39 other families with a history of multiple tumors, including leukemia, without finding additional inherited PAX5 mutations. The researchers also examined more than 500 additional cases of non-inherited B cell ALL and found mutations at the same position of the PAX5 gene in two more patients. These two individuals had also lost the other copy of PAX5 through partial deletion of chromosome 9 in their leukemic cells. The findings suggested that the PAX5 mutation and deletion of the second, non-mutated copy of PAX5 contribute to the development of leukaemia.
The PAX5 gene encodes a transcription factor, which is a protein that regulates the activity of other genes. Working in cells growing in the laboratory, investigators found evidence that the newly identified PAX5 mutant resulted in reduced expression of genes normally regulated by PAX5 in developing and mature B cells. St. Jude Children’s Research Hospital