Trisomy Disorders

Archive for the ‘chromosome disorder’ Category

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.



Molecular and Clinicopathologic Characterization of AML With Isolated Trisomy 4.

Mar 2012


Dept of Hematopathology, Unit 72, 1515 Holcombe Blvd, Houston, TX 77030.


Acute myeloid leukemia (AML) with isolated trisomy 4 is rare. Associations with KIT mutations on chromosome 4q12 have been documented. The clinicopathologic features and mutational status of KIT, FLT3, NPM1, CEBPA, and RAS were assessed in 13 AML cases with isolated trisomy 4. There were 9 men and 4 women with a median age of 54 years. Median blast count was 84% (range, 24%-93%). Morphologic features varied across five 2008 World Health Organization categories. FLT3 (5/10) and NPM1 (4/10) mutations were observed at a frequency similar to normal-karyotype AML cases. KIT D816V (1/10), RAS (1/11; NRAS), and CEBPA (0/9) mutations were rare or absent. In 11 of 13 cases, complete remission was achieved. In 8 cases, relapse occurred, with median relapse-free survival of 11 months. Median overall survival was 28 months. AML with isolated trisomy 4 is rare and associated with high bone marrow blast counts and an intermediate to poor prognosis. KIT mutations are uncommon.


A Human Stem Cell Model of Early Alzheimer’s Disease Pathology in Down Syndrome.

Feb 2012


Gurdon Institute and Department of Biochemistry, University of Cambridge,Tennis Court Road, Cambridge, CB2 1QN.


Human cellular models of Alzheimer’s disease (AD) pathogenesis would enable the investigation of candidate pathogenic mechanisms in AD and the testing and developing of new therapeutic strategies. We report the development of AD pathologies in cortical neurons generated from human induced pluripotent stem (iPS) cells derived from patients with Down syndrome. Adults with Down syndrome (caused by trisomy of chromosome 21) develop early-onset Alzheimer’s disease, probably due to increased expression of a gene on chromosome 21 that encodes the amyloid precursor protein (APP). We found that cortical neurons generated from iPS cells and embryonic stem (ES) cells from Down syndrome patients developed AD pathologies over months in culture, rather than years in vivo. These cortical neurons processed the transmembrane APP protein resulting in secretion of the pathogenic peptide fragment amyloid-β42 (Aβ42), which formed insoluble intracellular and extracellular amyloid aggregates. Production of Aβ peptides was blocked by a gamma-secretase inhibitor. Finally, hyperphosphorylated tau protein, a pathological hallmark of AD, was found to be localized to cell bodies and dendrites in iPS cell-derived cortical neurons from Down syndrome patients, recapitulating later stages of the AD pathogenic process.


Auditory function in the tc1 mouse model of down syndrome suggests a limited region of human chromosome 21 involved in otitis media.



Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom.


Down syndrome is one of the most common congenital disorders leading to a wide range of health problems in humans, including frequent otitis media. The Tc1 mouse carries a significant part of human chromosome 21 (Hsa21) in addition to the full set of mouse chromosomes and shares many phenotypes observed in humans affected by Down syndrome with trisomyof chromosome 21. However, it is unknown whether Tc1 mice exhibit a hearing phenotype and might thus represent a good model for understanding the hearing loss that is common in Down syndrome. In this study we carried out a structural and functional assessment of hearing in Tc1 mice. Auditory brainstem response (ABR) measurements in Tc1 mice showed normal thresholds compared to littermate controls and ABR waveform latencies and amplitudes were equivalent to controls. The gross anatomy of the middle and inner ears was also similar between Tc1 and control mice. The physiological properties of cochlear sensory receptors (inner and outer hair cells: IHCs and OHCs) were investigated using single-cell patch clamp recordings from the acutely dissected cochleae. Adult Tc1 IHCs exhibited normal resting membrane potentials and expressed all K(+) currents characteristic of control hair cells. However, the size of the large conductance (BK) Ca(2+) activated K(+) current (I(K,f)), which enables rapid voltage responses essential for accurate sound encoding, was increased in Tc1 IHCs. All physiological properties investigated in OHCs were indistinguishable between the two genotypes. The normal functional hearing and the gross structural anatomy of the middle and inner ears in the Tc1 mouse contrast to that observed in the Ts65Dn model of Down syndrome which shows otitis media. Genes that are trisomic in Ts65Dn but disomic in Tc1 may predispose to otitis media when an additional copy is active.


Clinical ocular manifestation of Patau’s syndrom (trisomy 13)–own observations


Kanigowska KGrałek MSeroczyńska M.


Z Kliniki Okulistyki Instytutu “Pomnik – Centrum Zdrowia Dziecka” w Warszawie.



The purpose of the article is to present the clinical abnormalities of Patau’s syndrome (trisomy13).


Examination was performed on 18 months old girl with trisomy13 in which we noted characteristic malformations in ocular system. The patient underwent cataract surgery and intraocular lens implantation in right eye. In this case the diagnosis of trisomy 13 was confirmed by karyotype.


Inferonasal iris colobomas, anterior-posterior form of persistent hyperplastic primary vitreus (PHPV), persistent tunica vasculosa lentis (PTVL), coloboma of the lens and cataract in right eye were found. Cataract surgery was performed with good results. Systemic abnormalities included heart defect, brain defect, cleft palate, small head, dysplastic ears, mental retardation, epilepsy and increased muscle tone.


The child with the presence of inferonosal iris colobomas and cataract and with other systemic and dysmorfic findings, should have kariotype examination to look for trisomy 13.


New report of two patients with mosaic trisomy 9 presenting unusual features and longer survival.

Dec 2011

Zen PRRosa RFRosa RCGraziadio CPaskulin GA.


Program and Clinical Geneticist, Universidade Federal de Ciências da Saúde de Porto Alegre.


Key words: Mosaicism. Chromosomes, human, pair 9. Chromosome aberrations. Goldenhar syndrome. Survivorship (Public health).

CONTEXT: Mosaic trisomy 9 is considered to be a rare chromosomal abnormality with limited survival. Our objective was to report on two patients with mosaic trisomy 9 presenting unusual findings and prolonged survival.


The first patient was a boy aged six years and five months presenting weight of 14.5 kg (< P3), height of 112 cm (P10), head circumference of 49 cm (P2), prominent forehead, triangular and asymmetric face, thin lips, right microtia with overfolded helix, small hands, micropenis (< P10), small testes and hallux valgus. His lymphocyte karyotype was mos 47,XY,+9 [4 ]/46,XY [50 ]. Additional cytogenetic assessment of the skin showed normal results. The second patient was a two-year-old girl who was initially assessed at five months of age, when she presented weight of 5.3 kg (< P3), height of 61.5 cm (P2-P10), head circumference of 40.5 cm (P25), sparse hair, micrognathia, right ear with overfolded helix and preauricular pit, triphalangeal thumbs and sacral dimple. She also had a history of congenital heart disease, hearing loss, hypotonia, delayed neuropsychomotor development and swallowing disorder. Her lymphocyte karyotype was mos 47,XX,+9 [3 ]/46,XX [69 ]. Both patients had unusual clinical findings (the first, hemifacial hypoplasia associated with microtia, with a phenotype of oculo-auriculo-vertebral spectrum, and the second, triphalangeal thumbs and hearing loss) and survival greater than what is usually described in the literature (< 1 year). Further reports will be critical for delineating the clinical features and determining the evolution of patients with mosaic trisomy 9.

SciElo Sao Paulo Medical Journal

Detection of 9p partial trisomy using array-based comparative genomic hybridization.

Feb 2012

[Article in Chinese]


Center of Prenatal Diagnosis, Nanjing Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210004, P. R. China.;



To detect chromosomal aberrations in a child with developmental delay and speech and language disorders in order to explore the underlying genetic causes of congenital malformation, and to investigate the feasibility of array-based comparative genomic hybridization (array-CGH) for molecular genetic diagnosis.


G-banding and array-CGH were applied to characterize the genetic abnormality in the three family members.


G-banding analysis revealed the affected child and the healthy mother are both carriers of inv(9)(p13q13), while the child has carried a chromosome fragment derived from chromosome 13. Array-CGH analysis indicated the derivative chromosome fragment has originated from 9p with breakpoints at around 9p13.1-p24.3.


Trisomy 9p13.1-p24.3 may be the cause of congenital malformation in the child. For its high resolution and high accuracy, array-CGH is a powerful tool for genetic analysis.



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