Trisomy Disorders

Posts Tagged ‘down syndrome

Noninvasive method accurately and efficiently detects risk of Down syndrome

February 2012

Using a noninvasive test on maternal blood that deploys a novel biochemical assay and a new algorithm for analysis, scientists can detect, with a high degree of accuracy, the risk that a fetus has the chromosomal abnormalities that cause Down syndrome and a genetic disorder known as Edwards syndrome. The new approach is more scalable than other recently developed genetic screening tests and has the potential to reduce unnecessary amniocentesis or CVS. Two studies evaluating this approach are available online in advance of publication in the April issue of the American Journal of Obstetrics & Gynecology(AJOG).

Diagnosis of fetal , or aneuploidies, relies on invasive testing by chorionic villous sampling or amniocentesis in pregnancies identified as high-risk. Although accurate, the tests are expensive and carry a risk of miscarriage. A technique known as massively parallel shotgun sequencing (MPSS) that analyzes cell-free DNA (cfDNA) from the mother’s plasma for fetal conditions has been used to detect trisomy 21 (T21) pregnancies, those with an extra copy of chromosome 21 that leads to , and trisomy 18 (T18), the chromosomal defect underlying . MPSS accurately identifies the conditions by analyzing the entire genome, but it requires a large amount of DNA sequencing, limiting its clinical usefulness.

Scientists at Aria Diagnostics in San Jose, CA developed a novel assay, Digital Analysis of Selected Regions (DANSR™), which sequences loci from only the chromosomes under investigation. The assay requires 10 times less DNA sequencing than MPSS approaches.

In the current study, the researchers report on a novel statistical, the Fetal-fraction Optimized Risk of Trisomy Evaluation (FORTE™), which considers age-related risks and the percentage of fetal DNA in the sample to provide an individualized risk score for trisomy. Explains author Ken Song, MD, “The higher the fraction of fetal cfDNA, the greater the difference in the number of cfDNA fragments originating from trisomic versus disomic [normal] chromosomes and hence the easier it is to detect trisomy. The FORTE algorithm explicitly accounts for fetal fraction in calculating trisomy risk.”

To test the performance of the DANSR/FORTE assay, Dr. Song and his colleagues evaluated a set of subjects consisting of 123 normal, 36 T21, and 8 T18 pregnancies. All samples were assigned FORTE odd scores for chromosome 18 and chromosome 21. The combination of DANSR and FORTE correctly identified all 36 cases of T21 and 8 cases of T18 as having a greater than 99% risk for each trisomy in a blinded analysis. There was at least a 1,000 fold magnitude sepa

In a related study, researchers from the Harris Birthright Research Centre for Fetal Medicine, Kings College Hospital, University of London and the University College London Hospital, University College London, provided 400 maternal plasma samples to Aria for analysis using the DANSR assay with the FORTE algorithm. The subjects were all at risk for aneuploidies, and they had been tested by chorionic villous sampling. The analysis distinguished all cases of T21 and 98% of T18 cases from euploid pregnancies. In all cases of T21, the estimated risk for this aneuploidy was greater than or equal to 99%, whereas in all normal pregnancies and those with T18, the risk score for T21 was less than or equal to 0.01%.

“Combining the DANSR assay with the FORTE algorithm provides a robust and accurate assessment of fetal trisomy risk,” says Dr. Song. “Because DANSR allows analysis of specific genomic regions, it could be potentially used to evaluate genetic conditions other than trisomy. The incorporation of additional risk information, such as from ultrasonography, into the FORTE algorithm warrants investigation.”

Kypros H. Nicolaides, MD, senior author of the University of London study, suggests that fetal trisomy evaluation with cfDNA testing will inevitably be introduced into clinical practice. “It would be useful as a secondary test contingent upon the results of a more universally applicable primary method of screening. The extent to which it could be applied as a universal screening tool depends on whether the cost becomes comparable to that of current methods of sonographic and biochemical testing.”

Dr. Nicolaides also notes that the plasma samples were obtained from high-risk pregnancies where there is some evidence of impaired placental function. It would also be necessary to demonstrate that the observed accuracy with cfDNA testing obtained from the investigation of pregnancies at high-risk for aneuploidies is applicable to the general population where the prevalence of fetal trisomy 21 is much lower. “This may well prove to be the case because the ability to detect aneuploidy with cfDNA is dependent upon assay precision and fetal DNA percentage in the sample rather than the prevalence of the disease in the study population,” he concludes.



Increased dosage of the chromosome 21 ortholog Dyrk1a promotes megakaryoblastic leukemia in a murine model of Down syndrome.

Feb 2012


Individuals with Down syndrome (DS; also known as trisomy 21) have a markedly increased risk of leukemia in childhood but a decreased risk of solid tumors in adulthood. Acquired mutations in the transcription factor-encoding GATA1 gene are observed in nearly all individuals with DS who are born with transient myeloproliferative disorder (TMD), a clonal preleukemia, and/or who develop acute megakaryoblastic leukemia (AMKL). Individuals who do not have DS but bear germline GATA1 mutations analogous to those detected in individuals with TMD and DS-AMKL are not predisposed to leukemia. To better understand the functional contribution of trisomy 21 to leukemogenesis, we used mouse and human cell models of DS to reproduce the multistep pathogenesis of DS-AMKL and to identify chromosome 21 genes that promote megakaryoblastic leukemia in children with DS. Our results revealed that trisomy for only 33 orthologs of human chromosome 21 (Hsa21) genes was sufficient to cooperate with GATA1 mutations to initiate megakaryoblastic leukemia in vivo. Furthermore, through a functional screening of the trisomic genes, we demonstrated that DYRK1A, which encodes dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A, was a potent megakaryoblastic tumor-promoting gene that contributed to leukemogenesis through dysregulation of nuclear factor of activated T cells (NFAT) activation. Given that calcineurin/NFAT pathway inhibition has been implicated in the decreased tumor incidence in adults with DS, our results show that the same pathway can be both proleukemic in children and antitumorigenic in adults.

Journal of Clinical Investigation

Herron: Down syndrome an oft misunderstood disorder
By Mason Herron / Columnist
published: Tue, 15 Sep, 2009

When we reflect upon the progress humanity has made, we often reach two conclusions: praise for the progress and the heroes that brought it and the realization of how much more progress must be made. Historically speaking, there are a plethora of examples to this law: colonialism, religious tolerance, civil rights, gender equality, etc.

You get the idea. Perhaps, then, we might consider these reflections and apply them to an issue of today that might not be as eminent but is nonetheless in dire need of grave reflection and consideration, and that is the way we perceive the nature of Down syndrome.

Down syndrome — also referred to as trisomy 21 — is a disorder brought on by the presence of an additional chromosome in an individual’s genes. People who have the disorder are typically developmentally disabled and display below-average cognitive ability. Physical characteristics include low muscle tone, almond-shaped eyes, a flat nasal bridge, a protruding tongue and a number of other features. Each individual might experience these characteristics with different intensities and variability.Down syndrome occurs in one of every 800 births, and the risk of conceiving a child with Down syndrome increases as women grow older, with women older than 35 having 80 percent of Down syndrome births.
 Our understanding of Down syndrome — and the way it was portrayed — was, until recently, simple at best and cruel at worst. The disorder was popularly referred to as “mongolism” (in reference to a Mongoloid race), and the term still creeps its way into modern medical texts. Worse, however, was the implementation of a policy in the early 20th century by 33 of 48 states that mandated that individuals with Down syndrome be forced to undergo involuntary sterilization, and many were murdered by Nazi Germany’s “Action T4” euthanasia program.

This history reveals not only a lack of ethics in regard to the mentally disabled, but also a severe underestimation of the capabilities of those who are born with Down syndrome. A generation after many of those with Down syndrome would have been institutionalized, many are able to happily live and work independently. Many are also perfectly literate, and I hope I need not point out the remarkable athletic talent and leadership displayed at Special Olympics events across the country.

But then one reads this: “It is crucial to reaffirm the morality of aborting a fetus diagnosed with Down syndrome … Because a person afflicted with Down syndrome is only capable of being marginally productive (if at all),” Nicholas Provenzo, founder of the Center for the Advancement of Capitalism, said.

Perhaps no one has said it better than online blogger, Diana Hsieh. “[Christians] would regard abortion as a moral way to prevent the infliction of a miserable, degraded life on the person that will emerge from the womb. Instead, they want to create more mentally defective and perpetually dependent children by outlawing abortion.”

A 2002 study revealed that 91 to 93 percent of Down syndrome pregnancies were intentionally terminated. Many potential parents are unwilling to take on the burdens and uncertainties of raising a disabled child. However, these fears are often exacerbated by a misunderstanding of Down syndrome. According to a congressional testimony by Dr. Brian Skotko, mothers included in his study that had been diagnosed as having a Down syndrome pregnancy “reported that doctors did not tell them about the positive potential of people with Down syndrome, nor did they feel like they received enough up-to-date information or contact information for parent support groups.”

Efforts have been made to rectify this concern. The bi-partisan Prenatally and Postnatally Diagnosed Conditions Awareness Act, signed by President Bush in October 2008, is a bill that seeks to inform and educate the public about Down syndrome and other prenatally or postnatally diagnosed disorders. Fortunately, government has not been the only instrument used toward the proliferation of information regarding Down syndrome. Many organizations, including the National Association for Down Syndrome, the National Down Syndrome Society and the Down Syndrome Association of Pittsburgh, have done work to educate others about this condition, as well.

It seems our immediate impressions of people often get the best of us. In the eyes of some, those with Down syndrome live an incomplete life, an unfair life. Yet we must realize this is not always the case and that those with Down syndrome shouldn’t be defined by their disorder. By willfully changing our perceptions on this particular issue, we take a step toward contributing to the progress of humanity as a whole.

E-mail Mason at


Molecular genetic analysis of Down syndrome.

Hum Genet. 2009 Jul

Patterson D.
Eleanor Roosevelt Institute, University of Denver, 2101 E. Wesley Avenue, Denver, CO 80208-6600, USA.

Down syndrome (DS) is caused by trisomy of all or part of human chromosome 21 (HSA21) and is the most common genetic cause of significant intellectual disability. In addition to intellectual disability, many other health problems, such as congenital heart disease, Alzheimer’s disease, leukemia, hypotonia, motor disorders, and various physical anomalies occur at an elevated frequency in people with DS. On the other hand, people with DS seem to be at a decreased risk of certain cancers and perhaps of atherosclerosis. There is wide variability in the phenotypes associated with DS. Although ultimately the phenotypes of DS must be due to trisomy of HSA21, the genetic mechanisms by which the phenotypes arise are not understood. The recent recognition that there are many genetically active elements that do not encode proteins makes the situation more complex.

Additional complexity may exist due to possible epigenetic changes that may act differently in DS. Numerous mouse models with features reminiscent of those seen in individuals with DS have been produced and studied in some depth, and these have added considerable insight into possible genetic mechanisms behind some of the phenotypes. These mouse models allow experimental approaches, including attempts at therapy, that are not possible in humans. Progress in understanding the genetic mechanisms by which trisomy of HSA21 leads to DS is the subject of this review.


Triple-marker prenatal screening program for chromosomal defects.

Obstet Gynecol. 2009 Jul

Kazerouni NN, Currier B, Malm L, Riggle S, Hodgkinson C, Smith S, Tempelis C, Lorey F, Davis A, Jelliffe-Pawlowski L, Walton-Haynes L, Roberson M.
Genetic Disease Screening Program, California Department of Public Health, Richmond, California, USA.

OBJECTIVE: To examine screening performance of California’s triple-marker screening program, using data from a statewide registry for chromosomal defects.

METHODS: This study included 752,686 women who received a screening risk and had an expected date of delivery between July 2005 and the end of June 2007. Follow-up diagnostic services for screen-positive women were performed at state-approved centers. Data on diagnostic outcomes from these visits were entered into the California Chromosomal Defect Registry (CCDR). Other CCDR sources include mandatory reporting by all cytogenetic laboratories and hospitals and outcome data forms submitted by prenatal care providers. RESULTS: The observed detection rate for Down syndrome (N=1,217) was 77.4%. It varied significantly by gestational dating method and maternal age. The rates for women aged younger than 35 years and 35 years and older were 62.4% and 94.0%, respectively. The detection rates were 81.3% for ultrasound-dated pregnancies and 67.5% for last menstrual period-dated pregnancies. For Turner syndrome, trisomy 18, triploidy, and trisomy 13, the detection rates were 79.4%, 82.5%, 98.1%, and 36.0%, respectively. The positive rate for Down syndrome was 5.4%. Of women with a Down syndrome fetus who were screen positive, only 49.5% opted for amniocentesis. Of women who obtained results from amniocentesis indicating a Down syndrome fetus, 61.4% had an elective termination, 26.2% had a live birth, 4.5% had a death or miscarriage, and 7.9% had an unknown outcome.

CONCLUSION: The observed performance of this large triple-marker screening program exceeds generally predicted detection rates for Down syndrome. This study methodology will be used to measure the performance of subsequent screening enhancements.

Lippincott, Wilkins & Williams

Congenital gastrointestinal defects in Down syndrome: a report from the Atlanta and National Down Syndrome Projects.

Clin Genet. 2008 Nov 17

Freeman SB, Torfs CP, Romitti PA, Royle MH, Druschel C, Hobbs CA, Sherman SL.
Department of Human Genetics, Emory University, Atlanta, GA, USA.

We report Down syndrome (DS)-associated congenital gastrointestinal (GI) defects identified during a 15 year, population-based study of the etiology and phenotypic consequences of trisomy 21. Between 1989 and 2004, six sites collected DNA, clinical and epidemiological information on live-born infants with standard trisomy 21 and their parents. We used chi-squared test and logistic regression to explore relationships between congenital GI defects and infant sex, race, maternal age, origin of the extra chromosome 21, and presence of a congenital heart defect. Congenital GI defects were present in 6.7% of 1892 eligible infants in this large, ethnically diverse, population-based study of DS. Defects included esophageal atresia/tracheoesophageal fistula (0.4%), pyloric stenosis (0.3%), duodenal stenosis/atresia (3.9%), Hirschsprung disease (0.8%), and anal stenosis/atresia (1.0%). We found no statistically significant associations between these defects and the factors examined. Although not significant, esophageal atresia was observed more often in infants of younger mothers and Hispanics, Hirschsprung disease was more frequent in males and in infants of younger mothers and blacks, and anal stenosis/atresia was found more often among females and Asians.


Congenital heart disease in children with Down’s syndrome: Turkish experience of 13 years.

Acta Cardiol. 2008 Oct

Nisli K, Oner N, Candan S, Kayserili H, Tansel T, Tireli E, Karaman B, Omeroglu RE, Dindar A, Aydogan U, Başaran S, Ertugrul T.
Paediatric Cardiology Division, Paediatrics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.

BACKGROUND: Down’s syndrome (DS) is the most common chromosomal abnormality due to a trisomy of chromosome 21 commonly associated with congenital heart defects (CHDs). This study aimed to evaluate the frequency and types of CHD patterns in Turkish children with DS.

METHOD: The data relate to paediatric patients with DS who underwent cardiologic screening between 1994 and 2007 and were reviewed in our Paediatric Cardiology unit.

RESULTS: Four hundred and twenty-one out of the 1042 paediatric patients with DS studied over a 13-year period had associated CHD. Of these, 320 (77.6%) had a single cardiac lesion, while the remaining 92 patients (22.4%) had multiple defects. The most common single defect was an atrioventricular septal defect (AVSD) found in 141 patients (34.2%), followed by 69 patients (16.7%) showing secundum type atrial septal defect, and ventricular septal defect in 68 patients (16.5%). AVSDs were the leading type, isolated or combined with other cardiac anomalies with an overall occurrence of 19.8% of paediatric patients with DS, and 49.2% of paediatric patients with both DS and CHD.

CONCLUSION: This is the first study concerning the frequency and type of CHD observed in Turkish children with DS. The high frequency ofAVSD in Turkish children with DS implied that early screening for CHDs by echocardiography is crucial. The correction of AVSDs in paediatric patients with DS should be performed in the first 6 months of life to avoid irreversible haemodynamic consequences of the defect.

PMID: 19014001 [PubMed – in process]

May 2018
« Jan    

Blog Stats

  • 89,144 hits

Top Posts