Verinata Health, Inc.

Affymetrix, Inc.

Massachusetts Institute of Technology

Illumina Corporation

Affymax Technologies, N.v.

Other

Grail, Inc.

Affyemtrix, Inc.

Affymetrix Technologies, N.v.

Richard P Rava

Glenn H McGall

Brian K Rhees

Martin J Goldberg

David A Comstock

Stephen P Fodor

Mark O Trulson

Manjula Chinnappa

Gabrielle Heilek

Stephen P A Fodor

Michael S Feld

Anupama Srinivasan

Darya Chudova

Robert J Lipshutz

Rolfe C Anderson

Earl A Hubbell

Jennifer Dee Tan

Yue-Jen Chuu

Martin Diggelman

Joseph J Baraga

Ian Walton

MacDonald S Morris

Nam Quoc Ngo

Ngo Quoc Nam

Lubert Stryer

James L Winkler

David Stern

Rebecca Rae Richards-Kortum

Peter J Fiekowsky

Virginia W Goss

R Fabian Pease

John P Burke

Michael W Hunkapiller

Melvin Yamamoto

Catalin Barbacioru

Mel Yamamoto

Sven Duenwald

Stephen R Quake

Keith W Jones

Carter Kittrell

Ramachandra Rac Dasari

Haim Kedar

Lisa T Kajisa

Bei-Shen Sywe

Gengxin Chen

Dimitri Skvortsov

Dana Truong

Robert M Cothren

Lucene Tong

Paola Taroni

Kyungwon An

Young D Park

Anand V Mehta

Alex Aravanis

Arash Jamshidi

Gordon M Cann

Diana Abdueva

Irving Itzkan

Macdonald S Morris

Jeffrey H Sugarman

Gary B Hayes

Jun Wu

Vernon A Norviel

Rick Klausner

Douglas Albagli

Joseph A Izatt

Firooz Partovi

Jeffrey J Sugarman

Brian Kent Rhees

SEQUENCING METHODS AND COMPOSITIONS FOR PRENATAL DIAGNOSES

The present invention relates to methods comprising identifying polymorphisms in samples comprising mixtures of genomes, and for determining and/or monitoring the presence or absence of disorders associated with the identified polymorphisms.

Identification of polymorphic sequences in mixtures of genomic DNA

The present invention provides a method capable of detecting single or multiple fetal chromosomal aneuploidies in a maternal sample comprising fetal and maternal nucleic acids, and verifying that the correct determination has been made. The method is applicable to determining copy number variations (CNV) of any sequence of interest in samples comprising mixtures of genomic nucleic acids derived from two different genomes, and which are known or are suspected to differ in the amount of one or more sequence of interest. The method is applicable at least to the practice of noninvasive prenatal diagnostics, and to the diagnosis and monitoring of conditions associated with a difference in sequence representation in healthy versus diseased individuals.

Normalizing chromosomes for the determination and verification of common and rare chromosomal aneuploidies

The invention provides compositions and methods for determining the fraction of fetal nucleic acids in a maternal sample comprising a mixture of fetal and maternal nucleic acids. The fraction of fetal nucleic acids can be used in determining the presence or absence of fetal aneuploidy.

Methods for determining fraction of fetal nucleic acids in maternal samples

The invention provides compositions and methods for simultaneously determining the presence or absence of fetal aneuploidy and the relative amount of fetal nucleic acids in a sample obtained from a pregnant female. The method encompasses the use of sequencing technologies and exploits the occurrence of polymorphisms to provide a streamlined noninvasive process applicable to the practice of prenatal diagnostics.

Simultaneous determination of aneuploidy and fetal fraction

The invention provides methods for determining aneuploidy and/or fetal fraction in maternal samples comprising fetal and maternal cfDNA by massively parallel sequencing. The method comprises a novel protocol for preparing sequencing libraries that unexpectedly improves the quality of library DNA while expediting the process of analysis of samples for prenatal diagnoses.

Sequencing methods and compositions for prenatal diagnoses

The invention provides a method for determining copy number variations (CNV) of a sequence of interest in a test sample that comprises a mixture of nucleic acids that are known or are suspected to differ in the amount of one or more sequence of interest. The method comprises a statistical approach that accounts for accrued variability stemming from process-related, interchromosomal and inter-sequencing variability. The method is applicable to determining CNV of any fetal aneuploidy, and CNVs known or suspected to be associated with a variety of medical conditions. CNV that can be determined according to the method include trisomies and monosomies of any one or more of chromosomes 1-22, X and Y, other chromosomal polysomies, and deletions and/or duplications of segments of any one or more of the chromosomes, which can be detected by sequencing only once the nucleic acids of a test sample.

Analyzing copy number variation in the detection of cancer

Detecting and classifying copy number variation

Disclosed are methods for determining at least one sequence of interest of a fetus of a pregnant mother. In various embodiments, the method can determine one or more sequences of interest in a test sample that comprises a mixture of maternal cellular DNA and mother-and-fetus cfDNA. In some embodiments, methods are provided for determining whether the fetus has a genetic disease. In some embodiments, methods are provided for determining whether the fetus is homozygous in a disease causing allele when the mother is heterozygous of the same allele. In some embodiments, methods are provided for determining whether the fetus has a copy number variation (CNV) or a non-CNV genetic sequence anomaly.

Non-invasive prenatal diagnosis of fetal genetic condition using cellular DNA and cell free DNA

Provided herein are methods of enriching mutated cell free nucleic acids for detection and diagnosis of cancer. Also provided are methods using a CRISPR-Cas system to target and deplete unwanted more abundant cell free nucleic acid sequences thereby enriching for less abundant sequences.

Enrichment of mutated cell free nucleic acids for cancer detection

Disclosed are methods for determining copy number variation (CNV) known or suspected to be associated with a variety of medical conditions. In some embodiments, methods are provided for determining copy number variation of fetuses using maternal samples comprising maternal and fetal cell free DNA. In some embodiments, methods are provided for determining CNVs known or suspected to be associated with a variety of medical conditions. Some embodiments disclosed herein provide methods to improve the sensitivity and/or specificity of sequence data analysis by deriving a fragment size parameter. In some implementations, information from fragments of different sizes are used to evaluate copy number variations. In some implementations, one or more t-statistics obtained from coverage information of the sequence of interest is used to evaluate copy number variations. In some implementations, one or more fetal fraction estimates are combined with one or more t-statistics to determine copy number variations.

Using cell-free DNA fragment size to determine copy number variations

The invention provides a method for determining copy number variations (CNV) of a sequence of interest in a test sample that comprises a mixture of nucleic acids that are known or are suspected to differ in the amount of one or more sequence of interest. The method comprises a statistical approach that accounts for accrued variability stemming from process-related, interchromosomal and inter-sequencing variability. The method is applicable to determining CNV of any fetal aneuploidy, and CNVs known or suspected to be associated with a variety of medical conditions. CNV that can be determined according to the present method include trisomies and monosomies of any one or more of chromosomes 1-22, X and Y, other chromosomal polysomies, and deletions and/or duplications of segments of any one or more of the chromosomes, which can be detected by sequencing only once the nucleic acids of a test sample. Any aneuploidy can be determined from sequencing information that is obtained by sequencing only once the nucleic acids of a test sample.

Method for determining copy number variations

A method for determining copy number variations (CNV) of a sequence of interest in a test sample that comprises a mixture of nucleic acids that are known or are suspected to differ in the amount of one or more sequence of interest. The method comprises a statistical approach that accounts for accrued variability stemming from process-related, interchromosomal and inter-sequencing variability. The method is applicable to determining CNV of any fetal aneuploidy, and CNVs known or suspected to be associated with a variety of medical conditions.

Disclosed are methods for determining copy number variation (CNV) known or suspected to be associated with a variety of medical conditions. In some embodiments, methods are provided for determining copy number variation (CNV) of fetuses using maternal samples comprising maternal and fetal cell free DNA. In some embodiments, methods are provided for determining CNVs known or suspected to be associated with a variety of medical conditions. Some embodiments disclosed herein provide methods to improve the sensitivity and/or specificity of sequence data analysis by deriving a fragment size parameter, such as a size-weighted coverage or a fraction of fragments in a size range. In some embodiments, the fragment size parameter is adjusted to remove 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. Also disclosed are systems and computer program products for evaluation of CNV of sequences of interest.

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Richard P Rava