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Related Concept Videos

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The evolution of new genes is critical for speciation. Exon recombination, also known as exon shuffling or domain shuffling, is an important means of new gene formation. It is observed across vertebrates, invertebrates, and in some plants such as potatoes and sunflowers. During exon recombination, exons from the same or different genes recombine and produce new exon-intron combinations, which might evolve into new genes. 
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Antigen receptors are essential components of the immune system crucial in defending the body against foreign invaders. These receptors are present on the surface of B and T cells, enabling them to recognize antigens and mount an appropriate immune response.
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Single Nucleotide Polymorphisms-SNPs01:05

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A single nucleotide polymorphism or SNP is a single nucleotide variation at a specific genomic position in a large population. It is the most prevalent type of sequence variation found in the human genome. Point mutations that occur in more than 1% of the population qualify as SNPs. These are present once every 1000 nucleotides on an average in the human genome. Replacement of a purine with another purine (A/G) or a pyrimidine with another pyrimidine (C/T) is known as a transition. In contrast,...
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Point and Frameshift Mutations01:30

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Point mutations are genetic alterations involving the change of a single nucleotide base pair in DNA. Depending on how the alteration affects protein synthesis, they can lead to various consequences.Point mutations fall into the following types:Silent mutations occur when a nucleotide change does not alter the amino acid sequence due to the redundancy of the genetic code. For instance, changing ACC to ACA still encodes threonine, leaving the protein function unaffected. This occurs because...
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Antigen Processing Pathways01:31

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MHC molecules are key players in the immune response, enabling T cells to recognize and respond to specific antigens. They are present on the surface of all nucleated cells in the body and are instrumental in presenting antigens to T cells and activating them. T cells recognize the MHC-antigen complex and initiate an immune response. MHC class I and MHC class II are two main types of MHC molecules, each associated with a distinct antigen processing pathway.
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Sequencing of the human genome has opened up several best-kept secrets of the genome. Scientists have identified thousands of genome variations that exist within a population. These variations can be a single nucleotide or a larger chromosomal variation.
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Intronic branchpoint-to-acceptor variants underlying inborn errors of immunity.

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Journal of Human Immunity
|December 15, 2025
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Summary

Intronic variants, often overlooked, can cause inborn errors of immunity (IEI). This study confirms the pathogenicity of specific intronic variants using advanced bioinformatics and experimental methods, advocating for their inclusion in routine genetic screening.

Keywords:
Inborn error of immunitybranchpointgeneticsintronic variantspathogenicity

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Area of Science:

  • Genetics
  • Immunology
  • Bioinformatics

Background:

  • Clinical genetic testing primarily targets protein-coding regions, potentially missing pathogenic variants in intronic DNA.
  • Intronic variants require specialized bioinformatics and experimental validation to assess their impact on gene function and pathogenicity.
  • Inborn errors of immunity (IEI) are a group of genetic disorders affecting the immune system, often with complex genetic etiologies.

Purpose of the Study:

  • To identify and characterize pathogenic intronic variants in patients with unexplained inborn errors of immunity (IEI).
  • To demonstrate the utility of ad hoc bioinformatics tools and experimental validation for detecting and confirming the pathogenicity of intronic variants.
  • To advocate for the systematic screening and investigation of intronic variants in clinical diagnostic settings.

Main Methods:

  • Utilized ad hoc bioinformatics tools to screen intronic regions for potential pathogenic variants in a cohort of patients with unexplained IEI.
  • Identified specific branchpoint and AG-gain acceptor site variants within key immunodeficiency-related genes.
  • Confirmed variant deleteriousness and pathogenicity through exon-captured transcriptome studies and flow cytometry analysis of protein production/function.

Main Results:

  • Identified seven kindreds with pathogenic intronic variants across six distinct genes (BTK, SH2D1A, WAS, DOCK8, NFKB1, STXBP2, UNC13D).
  • Characterized three branchpoint variants and four AG-gain acceptor site variants located between -9 and -49 positions relative to the wild-type acceptor site.
  • Experimental validation confirmed the functional impact and pathogenicity of the identified intronic variants, linking them to unexplained IEI.

Conclusions:

  • Intronic variants, including branchpoint and cryptic splice site alterations, are a significant cause of unexplained inborn errors of immunity.
  • Advanced bioinformatics combined with functional studies provides a robust approach to identify and confirm the pathogenicity of intronic variants.
  • Systematic screening and investigation of intronic regions are crucial for comprehensive genetic diagnosis in IEI and potentially other genetic disorders.