Methods and systems for genetic analysis
Inventors
Bartha, Gabor T. • Chandratillake, Gemma • Chen, Richard • Garcia, Sarah • Lam, Hugo Yu Kor • Pratt, Mark R. • West, John
Assignees
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Publication Number
US-12371746-B2
Publication Date
2025-07-29
Expiration Date
Abstract
This disclosure provides systems and methods for sample processing and data analysis. Sample processing may include nucleic acid sample processing and subsequent sequencing. Some or all of a nucleic acid sample may be sequenced to provide sequence information, which may be stored or otherwise maintained in an electronic storage location. The sequence information may be analyzed with the aid of a computer processor, and the analyzed sequence information may be stored in an electronic storage location that may include a pool or collection of sequence information and analyzed sequence information generated from the nucleic acid sample. Methods and systems of the present disclosure can be used, for example, for the analysis of a nucleic acid sample, for producing one or more libraries, and for producing biomedical reports. Methods and systems of the disclosure can aid in the diagnosis, monitoring, treatment, and prevention of one or more diseases and conditions.
Core Innovation
The patent describes systems and methods for analyzing nucleic acid samples obtained from an individual for disease diagnosis and/or monitoring. The approach generates a first subset of nucleic acid molecules by contacting a nucleic acid sample with one or more pulldown probe sets that selectively enrich for an exome, and at least one pulldown probe set comprises 10 or more pulldown probes with different sequences.
A first sequencing assay is conducted on the first subset to yield a first result comprising a first nucleic acid sequence. With the aid of a computer processor, one or more primer sets are produced that are configured to selectively amplify a plurality of polymorphisms based on the first result, and the primer sets are used to generate a second subset from a second nucleic acid sample by selectively amplifying nucleic acid molecules to produce a set of amplicons, wherein the selectively amplifying comprises multiplex PCR.
A second sequencing assay is conducted on the set of amplicons to yield a second result comprising a second nucleic acid sequence, thereby analyzing the nucleic acid samples. The document further covers generating and using primer sets based on sequencing results, optionally combining sequencing results and producing biomedical reports, with reported sequencing performance improvements and metrics such as sensitivity/coverage and error rate/accuracy including Phred quality score (Q).
Claims Coverage
The provided portion includes one independent method claim (clm-00001). The claim centers on a two-stage workflow: exome enrichment followed by sequencing, computer-generated primer design for polymorphisms, multiplex PCR amplification into amplicons, and a second sequencing assay, thereby analyzing nucleic acid samples.
Exome-selective pulldown enrichment with plural probe sequences
Generating a first subset of nucleic acid molecules from a first nucleic acid sample by contacting the first nucleic acid sample with one or more pulldown probe sets that selectively enrich for an exome, wherein at least one pulldown probe set comprises 10 or more pulldown probes with different sequences.
First sequencing assay yielding initial sequence result
Conducting a first sequencing assay on the first subset of nucleic acid molecules to yield a first result comprising a first nucleic acid sequence.
Computer-processor primer set generation for polymorphisms
Producing, with the aid of a computer processor, one or more primer sets configured to selectively amplify a plurality of polymorphisms, wherein the plurality of polymorphisms are based on the first result obtained from the first sequencing assay.
Multiplex PCR amplification into amplicons from primer-selected targets
Generating a second subset from a second nucleic acid sample by selectively amplifying nucleic acid molecules with the one or more primer sets to produce a set of amplicons, wherein the selectively amplifying comprises multiplex PCR.
Second sequencing assay on amplicons yielding a second sequence result
Conducting a second sequencing assay on the set of amplicons to yield a second result comprising a second nucleic acid sequence, thereby analyzing the nucleic acid samples.
Overall, the claim coverage is directed to a sequential nucleic-acid analysis workflow in which exome-enriched molecules are first sequenced to obtain sequence information, computer-processor-produced primer sets target polymorphisms from that information for multiplex PCR amplification into amplicons, and a second sequencing assay provides a second sequence result for analyzing nucleic acid samples.
Stated Advantages
Sensitivity/coverage improvements for sequencing are reported.
Improved sequencing accuracy/error metrics are reported, including Phred quality score (Q).
Documented Applications
Disease diagnosis and/or disease monitoring using nucleic-acid genetic analysis based on sequencing results.
Biomedical reporting based on the sequencing results and/or combined assay results [application/reporting described in partial content].
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