Targeted sequencing of maternal plasma for haplotype-based non-invasive prenatal testing of spinal muscular atrophy

Objective.To describe the respiratory trajectories and their correlation with motor function in an international paediatric cohort of patients with type 2 and non-ambulant type 3 spinal muscular atrophy (SMA).Methods.Eight-year retrospective observational study of patients in the iSMAc natural history study. We retrieved anthropometrics, forced vital capacity (FVC) absolute, FVC% predicted (FVC%P.), Non-Invasive ventilation (NIV) requirement. Hammersmith functional motor scale (HFMS) and Revised performance of upper limb (RULM) were correlated with respiratory function. We excluded patients in interventional clinical trials and on Nusinersen commercial therapy.Results.There were 437 patients with SMA: 348 type 2, 89 non-ambulant type 3. Mean age at first visit was 6.9(±4.4) and 11.1(±4) years. In SMA type 2 FVC%P declined by 4.2%/year from 5 to 13 years, followed by a slower decline (1.0%/year). In type 3 FVC%P declined by 6.3%/year between 8 and 13 years, followed by a slower decline (0.9%/year). 39% SMA type 2 and 9% type 3 required NIV at median age 5.0(1.8-16.6) and 15.1(13.8-16.3) years. 84% SMA type 2 and 80% type 3 had scoliosis, 54% and 46% required surgery, which did not significantly affect respiratory decline. FVC%P positively correlated with HFMS and RULM in both subtypes.Conclusions.In SMA type 2 and non-ambulant type 3 lung function declines differently, with a common levelling after age 13 years. Lung and motor function correlated in both subtypes. Our data further defines the milder SMA phenotypes and provides novel information to benchmark the long-term efficacy of new treatments for SMA.

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Noninvasive prenatal testing for chromosome aneuploidies and subchromosomal microdeletions/microduplications in a cohort of 42,910 single pregnancies with different clinical features

Human Genomics ◽

10.1186/s40246-019-0250-2 ◽

2019 ◽

Vol 13 (1) ◽

Cited By ~ 17

Author(s):

Yibo Chen ◽

Qi Yu ◽

Xiongying Mao ◽

Wei Lei ◽

Miaonan He ◽

...

Keyword(s):

Clinical Features ◽

Sex Chromosome ◽

Prenatal Testing ◽

Maternal Plasma ◽

Trisomy 13 ◽

Noninvasive Prenatal Testing ◽

Detection Rates ◽

Non Invasive ◽

Cell Free Fetal Dna ◽

Sex Chromosome Aneuploidies

Abstract Background Since the discovery of cell-free DNA (cfDNA) in maternal plasma, it has opened up new approaches for non-invasive prenatal testing. With the development of whole-genome sequencing, small subchromosomal deletions and duplications could be found by NIPT. This study is to review the efficacy of NIPT as a screening test for aneuploidies and CNVs in 42,910 single pregnancies. Methods A total of 42,910 single pregnancies with different clinical features were recruited. The cell-free fetal DNA was directly sequenced. Each of the chromosome aneuploidies and the subchromosomal microdeletions/microduplications of PPV were analyzed. Results A total of 534 pregnancies (1.24%) were abnormal results detected by NIPT, and 403 pregnancies had underwent prenatal diagnosis. The positive predictive value (PPV) for trisomy 21(T21), trisomy 18 (T18), trisomy 13 (T13), sex chromosome aneuploidies (SCAs), and other chromosome aneuploidy was 79.23%, 54.84%, 13.79%, 33.04%, and 9.38% respectively. The PPV for CNVs was 28.99%. The PPV for CNVs ≤ 5 Mb is 20.83%, for within 5–10 Mb 50.00%, for > 10 Mb 27.27% respectively. PPVs of NIPT according to pregnancies characteristics are also different. Conclusion Our data have potential significance in demonstrating the usefulness of NIPT profiling not only for common whole chromosome aneuploidies but also for CNVs. However, this newest method is still in its infancy for CNVs. There is still a need for clinical validation studies with accurate detection rates and false positive rates in clinical practice.

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Non-invasive prenatal testing for fetal inheritance of maternal β -thalassaemia mutations using targeted sequencing and relative mutation dosage: a feasibility study

BJOG An International Journal of Obstetrics & Gynaecology ◽

10.1111/1471-0528.15045 ◽

2018 ◽

Vol 125 (4) ◽

pp. 461-468 ◽

Cited By ~ 10

Author(s):

L Xiong ◽

AN Barrett ◽

R Hua ◽

SSY Ho ◽

L Jun ◽

...

Keyword(s):

Feasibility Study ◽

Prenatal Testing ◽

Targeted Sequencing ◽

Non Invasive

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Winging of the Scapula: The Underlying Biomechanics and an Orthotic Solution

Proceedings of the Institution of Mechanical Engineers Part H Journal of Engineering in Medicine ◽

10.1243/pime_proc_1995_209_348_02 ◽

1995 ◽

Vol 209 (4) ◽

pp. 215-223 ◽

Cited By ~ 8

Author(s):

N D Barnett ◽

M Mander ◽

J C Peacock ◽

K Bushby ◽

D Gardner-Medwin ◽

...

Keyword(s):

Muscular Dystrophy ◽

Surgical Technique ◽

Spinal Muscular Atrophy ◽

Nerve Injury ◽

Muscular Atrophy ◽

Sensor System ◽

Functional Improvement ◽

Medial Border ◽

Non Invasive ◽

Muscular Disorders

Winging of the scapula occurring in muscular disorders (muscular dystrophy and spinal muscular atrophy) or nerve injury has been investigated, resulting in a thorough understanding and presentation of the underlying biomechanics causing this occurrence. This includes a biomechanical explanation of the characteristic prominence of the medial border of the scapula upon attempted elevation, together with the biomechanical reasons for the rotation of the scapula in a direction contrary to the normal scapulohumeral rhythm. Based on these findings, a non-invasive alternative to the surgical technique for scapular stabilization has been devised, using an inflatable orthosis, placed between the scapula and an external restraint (such as a spinal jacket). The device has been tested on one subject using a 3SPACE™ Isotrak™ electromagnetic source and sensor system, and gave encouraging results. Elevation increased by up to 35° (37 per cent), and functional improvement in the use of the hand around the head and face has been achieved. The technique needs no aftercare or physiotherapy and is therefore both economical and functionally effective.

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Non-invasive prenatal testing (NIPT): limitations on the way to become diagnosis

Diagnosis ◽

10.1515/dx-2015-0002 ◽

2015 ◽

Vol 2 (3) ◽

pp. 141-158 ◽

Cited By ~ 15

Author(s):

Ioanna Kotsopoulou ◽

Panagiota Tsoplou ◽

Konstantinos Mavrommatis ◽

Christos Kroupis

Keyword(s):

Prenatal Testing ◽

Maternal Plasma ◽

Screening Tests ◽

Positive Finding ◽

Non Invasive ◽

Cell Free Fetal Dna ◽

The Future ◽

The Moment ◽

Next Generation Sequencing Ngs ◽

Near Future

AbstractWith the discovery of existing circulating cell-free fetal DNA (ccffDNA) in maternal plasma and the advent of next-generation sequencing (NGS) technology, there is substantial hope that prenatal diagnosis will become a predominately non-invasive process in the future. At the moment, non-invasive prenatal testing (NIPT) is available for high-risk pregnancies with significant better sensitivity and specificity than the other existing non-invasive methods (biochemical and ultrasonographical). Mainly it is performed by NGS methods in a few commercial labs worldwide. However, it is expected that many other labs will offer analogous services in the future in this fast-growing field with a multiplicity of in-house methods (e.g., epigenetic, etc.). Due to various limitations of the available methods and technologies that are explained in detail in this manuscript, NIPT has not become diagnostic yet and women may still need to undergo risky invasive procedures to verify a positive finding or to secure (or even expand) a negative one. Efforts have already started to make the NIPT technologies more accurate (even at the level of a complete fetal genome) and cheaper and thus more affordable, in order to become diagnostic screening tests for all pregnancies in the near future.

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Non-invasive prenatal testing for fetal aneuploidy by massively parallel DNA sequencing of maternal plasma: the future has arrived today/Nicht-invasiver Pränatal-Test auf fetale Aneuploidie mittels massiv-paralleler DNA-Sequenzanalyse im mütterlichen Plasma: in der Zukunft angekommen

LaboratoriumsMedizin ◽

10.1515/labmed-2012-0029 ◽

2012 ◽

Vol 36 (5) ◽

Cited By ~ 2

Author(s):

Amy Swanson ◽

Christin Coffeen ◽

Amy J. Sehnert

Keyword(s):

Massively Parallel Sequencing ◽

Prenatal Testing ◽

The United States ◽

Maternal Blood ◽

Maternal Plasma ◽

Massively Parallel ◽

Clinical Implementation ◽

Maternal Cell ◽

Non Invasive ◽

Fetal Aneuploidy

AbstractAfter decades of research, non-invasive prenatal testing (NIPT) using maternal blood to determine fetal chromosome status has found its way from the research laboratory into clinical practice, triggering a long-awaited paradigm shift in prenatal care. A variety of methods using sequencing of maternal cell-free DNA (cfDNA) have now been studied, primarily demonstrating their ability to detect the most common fetal aneuploidy, trisomy 21 (T21). The focus of this article is on massively parallel sequencing (MPS) with optimized sequence tag mapping and chromosome quantification, which accurately detects T21 as well as multiple other aneuploidies across the genome. The power of this technique resides in its high precision and reduction of variation within and between sequencing runs. Using MPS, classification of aneuploidy status for a given sample can be reliably assigned from the genetic information alone without the need to factor in other maternal pre-test risk or other clinical variables. Performance of this method has been prospectively demonstrated in a rigorous, blinded, multi-center study in the United States. The findings suggest that MPS can be incorporated into existing prenatal screening algorithms to reduce unnecessary invasive procedures. This technology and key considerations for clinical implementation are discussed.

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