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Single immunoglobulin interleukin-1 receptor related (sigirr) variants and uses thereof

A technology of protein and nucleic acid molecules, applied in the field of genetics, can solve problems such as insufficient understanding of inflammatory bowel disease and patients not being genetically diagnosed

Pending Publication Date: 2020-07-03
REGENERON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the genetic makeup of early-onset inflammatory bowel disease (EO-IBD) is poorly understood, and most patients remain genetically undiagnosed

Method used

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  • Single immunoglobulin interleukin-1 receptor related (sigirr) variants and uses thereof
  • Single immunoglobulin interleukin-1 receptor related (sigirr) variants and uses thereof
  • Single immunoglobulin interleukin-1 receptor related (sigirr) variants and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0207] Example 1: Patient recruitment and phenotyping

[0208] Whole-exome sequencing and trio-based variant analysis were performed on a 13-year-old patient with EO-IBD, his IBD-affected mother, and his unaffected father. The family has been probed for genetic evaluation of the patient for EO-IBD.

Embodiment 2

[0209] Example 2: Genomic samples

[0210] Genomic DNA was extracted from peripheral blood samples and transferred to the Regeneron Genetics Center (RGC) for whole exome sequencing and stored at -80°C in an automated biobank. Fluorescence-based quantification is performed to ensure DNA quantity and quality suitable for sequencing purposes.

[0211] 1 μg of DNA was sheared to an average fragment length of 150 base pairs (Covaris LE220) and prepared for exome capture with a custom kit from Kapa Biosystems. Samples were captured using NimbleGen SeqCap VCRome2.1 or Integrated DNA Technologies xGen Exome Target Design. Samples were barcoded, pooled and multiplexed for sequencing on an Illumina HiSeq 2500 using 75bp paired-end sequencing with v4 chemistry. Captured fragments were sequenced to achieve a minimum of 85% coverage of target bases at 20-fold or greater coverage. Following sequencing, data were processed using a cloud-based pipeline developed at RGC that uses DNAnexus a...

Embodiment 3

[0212] Example 3: Genomic Data Analysis

[0213]Standard quality control filters for minimum read depth (>10), genotype quality (>30), and allelic balance (>20%) were applied to the identified variants. Annotation and analysis pipelines developed using RGCs classify and annotate passing variants (whether synonymous, non-synonymous, spliced, frameshifted, or non-frameshifted) based on their potential functional impact. Family relationships were verified by measures derived from ancestry identity from genetic data using PRIMUS (Staples et al., Amer. J. Human Genet., 2014, 95, 553-564) and cross-referencing with pedigrees reported for this family to Infer associations and relationships within groups.

[0214] Given the reported family history, pedigree-based variant analysis and segregation were performed to identify candidate disease genes under an autosomal dominant pattern of inheritance. Variants that were shared between the affected proband and his affected mother but not ...

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Abstract

The disclosure provides nucleic acid molecules, including cDNA, comprising an alteration that encodes a truncated human Single Immunoglobulin Interleukin-1 Receptor Related (SIGIRR) protein. The disclosure also provides isolated and recombinant human SIGIRR protein variants that comprise a truncation at a position corresponding to position 215. The truncation, and the nucleic acid molecules encoding this change, associate with early-onset inflammatory bowel disease (EO-IBD). The disclosure also provides methods for determining whether a subject has or has a risk of developing EO-IBD, based onthe identification of such alterations in the nucleic acid molecules encoding SIGIRR.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application Serial No. 62 / 554,857, filed September 6, 2017, which is hereby incorporated by reference in its entirety. [0003] References to Sequence Listings [0004] This application includes a sequence listing electronically filed as a text file named 18923800602SEQ, created on August 30, 2018, and 56 kilobytes in size. The Sequence Listing is incorporated herein by reference. technical field [0005] The present disclosure relates generally to the field of genetics. More particularly, the present disclosure relates to genetic alterations in Single Immunoglobulin Interleukin-1 Receptor Related (SIGIRR) associated with, for example, early-onset inflammatory bowel disease (EO-IBD) and Polypeptide variants. Background technique [0006] Various references, including patents, patent applications, accession numbers, technical articles, and scholarly articles, are ci...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/6883
CPCC12Q1/6883C12Q2600/156G01N2800/065
Inventor C·G·贡萨加-贾雷吉J·霍罗威茨
Owner REGENERON PHARM INC