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Detecting fetal sub-chromosomal aneuploidies and copy number variations

A technology for copy number variation and chromosomes, applied in the fields of climate sustainability, electrical digital data processing, special data processing applications, etc., which can solve the problems of difficult and reliable detection of copy number variation, insufficient sensitivity, limiting signal, etc.

Active Publication Date: 2017-05-31
VERINATA HEALTH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, for genetic diseases involving shorter genetic sequences, the signal-to-noise ratio of existing methods may be too low for reliable detection of copy number variations
For example, many subchromosomal genetic syndromes involve sequences on the order of several megabases, limiting assays to determine the signal of CNVs
[0010] Limitations of existing methods for non-invasive prenatal diagnosis, which include insufficient sensitivity derived from short syndrome-associated sequences, limiting levels of cfDNA, and sequencing bias of techniques derived from the inherent nature of genomic information, pose challenges to meeting There is a continuing need for non-invasive methods that provide any or all of sensitivity, specificity, and utility to reliably diagnose copy number alterations in a variety of clinical settings

Method used

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  • Detecting fetal sub-chromosomal aneuploidies and copy number variations
  • Detecting fetal sub-chromosomal aneuploidies and copy number variations
  • Detecting fetal sub-chromosomal aneuploidies and copy number variations

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0479] Sequencing and preparation of primary and enriched sequencing libraries

[0480] a. Sequencing library preparation - abbreviated protocol (ABB)

[0481] All sequencing libraries, primary and enriched, were prepared from approximately 2 ng of purified cfDNA extracted from maternal plasma. Use as follows Library preparation was performed with reagents from the NEBNext™ DNA Sample Prep DNA Reagent Set 1 (Catalog No. E6000L; New England Biolabs, Ipswich, MA). Because cell-free plasma DNA fragments naturally, no further fragmentation by sonication or nebulization was performed on plasma DNA samples. according to The end repair module converts the overhangs of approximately 2 ng of purified cfDNA contained in 40 μl to phosphorylated blunt ends by incubating cfDNA with 5 μl 10X phosphorylation buffer, 2 μl deoxygenated nuclei in a 1.5 ml microcentrifuge tube at 20 °C Nucleotide solution mixture (10 mM each dNTP), 1 μl of a 1:5 dilution of DNA polymerase I, 1 μl of T4 DNA...

Embodiment 2

[0490] Accurate aneuploidy detection in twin pregnancies

[0491] introduce

[0492]Noninvasive prenatal testing (NIPT) of total cell-free DNA (cfDNA) using whole-genome massively parallel sequencing has been shown to be a very accurate and robust method for detecting fetal chromosomal aneuploidy. See, Bianchi DW, Platt LD, Goldberg JD, et al., Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol 2012;119:890- 901; Fan HC, Blumenfeld YJ, Chitkara U, Hudgins L, Quake SR. Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood. blood).Proc Natl Acad Sci U S A 2008;105:16266-71; Sehnert AJ, RheesB, Comstock D, et al. Optimal detection of fetal chromosomal abnormalities by massively parallel DNA sequencing of cell-free DNA from maternal blood ( Optimal detection of fetal chromosome abnormalities by massively parallel DNA sequencing of cell-free fetal DNA from maternal blood). Clin Chem 2011;57:1042-9. The test ...

Embodiment 3

[0514] Example 3: Syndrome-specific systematic bias removal pathway (SSS-BER)

[0515] introduction

[0516] Various non-invasive prenatal diagnosis (NIPD) methods employ fetal-derived cfDNA that is available in maternal body fluids such as peripheral blood. A number of NIPD methods extract, sequence, and compare cfDNA from the maternal periphery to determine whether fetal cfDNA from pregnant mothers contains copy number variations in genetic sequences associated with disease or phenotypes. Extracted and sequenced cfDNA provides sequence reads, which are then mapped to a reference genome. Sequence reads that map to unique locations or sites on a reference genome are called sequence tags. The number of sequence tags mapped to the sequence of interest can be used to determine the copy number or copy number variation of the sequence of interest.

[0517] The number of sequence labels that map to a sequence of interest is called coverage. Coverage of regions or bins of genetic...

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Abstract

Disclosed are methods for determining copy number variation (CNV) known or suspected to be associated with a variety of medical conditions, including syndromes related to CNV of subchromosomal regions wherein the bins from the unaffected training samples used as controls have a coverage similar to the coverage of the region inspected for CNV. In some embodiments, methods are provided for determining CNV of fetuses using maternal samples comprising maternal and fetal cell free DNA. Some embodiments disclosed herein provide methods to improve the sensitivity and / or specificity of sequence data analysis by removing within-sample GC-content bias. In some embodiments, removal of within-sample GC-content bias is based on sequence data corrected for systematic variation common across unaffected training samples. In some embodiments, syndrome related biases in sample data are also removed to increase signal to noise ratio. Also disclosed are systems for evaluation of CNV of sequences of interest.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 005,877, entitled Detection of Fetal Subchromosomal Aneuploidy, filed May 30, 2014, under 35 U.S.C. § 119(e), which is incorporated herein by reference in its entirety for for all purposes. Background technique [0003] One of the key endeavors in human medical research is the discovery of genetic abnormalities that produce adverse health outcomes. In many cases, specific genes and / or key diagnostic markers have been identified in portions of the genome where abnormal copy numbers exist. For example, extra or missing copies of whole chromosomes are common genetic lesions in prenatal diagnosis. In cancer, loss or doubling of the copy number of whole chromosomes or chromosome segments, and higher level amplifications in specific regions of the genome commonly occur. [0004] Much of the information on copy number variations (CNVs) has been...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/68G06F19/18G06F19/22G16B20/10G16B20/20G16B30/10
CPCC12Q1/6869C12Q1/6858G16B20/00G16B30/00G16B20/10G16B30/10G16B20/20C12Q2535/122C12Q2537/16C12Q2537/165
Inventor D·I·楚多瓦D·阿卜杜瓦
Owner VERINATA HEALTH INC
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