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Related Concept Videos

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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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Related Experiment Video

Updated: Oct 17, 2025

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Detecting cryptic clinically relevant structural variation in exome-sequencing data increases diagnostic yield for

Eugene J Gardner1, Alejandro Sifrim2, Sarah J Lindsay1

  • 1Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, Hinxton CB10 1SA, UK.

American Journal of Human Genetics
|October 9, 2021
PubMed
Summary
This summary is machine-generated.

A new tool, InDelible, identifies structural variations (SVs) missed by standard genetic testing. This improves diagnosis for rare developmental disorders by detecting previously hidden genetic causes.

Keywords:
bioinformaticsdevelopmental disordersdiagnosticsinsertions/deletionsstructural variation

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Area of Science:

  • Genetics
  • Bioinformatics
  • Genomic Medicine

Background:

  • Structural variations (SVs), larger than 50 bp, are significant causes of genetic diseases, particularly rare developmental disorders (DDs).
  • Current diagnostic methods like chromosomal microarrays (CMAs) and exome sequencing (ES) often fail to detect certain pathogenic SVs, leaving patients undiagnosed.
  • Undetected SVs represent a critical gap in diagnosing genetic conditions.

Purpose of the Study:

  • To develop and validate a novel bioinformatics tool, InDelible, for detecting structural variations (SVs) missed by conventional genetic analyses.
  • To assess the utility of InDelible in increasing the diagnostic yield for severe developmental disorders (DDs) using large-scale sequencing data.
  • To identify novel pathogenic SVs in genes associated with DDs.

Main Methods:

  • Development of InDelible, a tool analyzing short-read sequencing data for split-read clusters indicative of SV breakpoints.
  • Application of InDelible to whole-exome sequencing data from 13,438 probands with severe DDs from the Deciphering Developmental Disorders (DDD) study.
  • Clinical review and validation of identified rare, damaging variants.

Main Results:

  • InDelible identified 63 rare, damaging variants in genes linked to DDs that were missed by standard genetic analysis methods.
  • Approximately half (30/63) of the identified variants were deemed plausibly pathogenic after clinical review.
  • The tool was particularly effective for variants sized 21-500 bp, increasing the detection of such pathogenic variants by 42.9% in the DDD cohort.
  • Seven de novo variants in the MECP2 gene were identified, accounting for 35.0% of all de novo protein-truncating variants in MECP2 within the study.

Conclusions:

  • InDelible offers a valuable framework for discovering pathogenic structural variations (SVs) often missed by standard analytical workflows.
  • The tool has the potential to significantly improve the diagnostic yield of exome sequencing (ES) for a wide spectrum of genetic diseases.
  • This advancement aids in diagnosing individuals with developmental disorders and other genetic conditions where conventional methods have failed.