The whole genome karyotype represents the sequence of large chromosomal segments that define an individual’s genotype, encompassing variants such as aneuploidies, balanced, and unbalanced translocations. Karyotype analysis is essential for identifying genetic risk factors, guiding diagnoses, and informing treatment and genetic counseling for constitutional disorders. Optical Genome Mapping (OGM) offers a high-resolution alternative to traditional microscopic karyotyping. We present OMKar, an automated tool that leverages OGM data to generate virtual karyotypes by processing structural variants (SVs) and copy number variants (CNVs) into a breakpoint graph. OMKar employs Integer Linear Programming to ensure chromosomal balance and identifies Eulerian paths to reconstruct chromosomes. In simulation tests, OMKar reconstruction achieved 88% precision and 95% recall for SV concordance and a 95% Jaccard score for CNV concordance. It was further validated on 154 clinical samples from ten different sites, where it successfully reconstructed 144 of the 154 karyotypes. OMKar identified genetic mechanisms for five disorders missed by traditional karyotyping, demonstrating its robustness in detecting constitutional disorders. The tool is publicly available at https://github.com/siavashre/OMKar .

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OMKar: Optical Map Based Automated Karyotyping of Genomes to Identify Constitutional Disorders

  • Siavash Raeisi Dehkordi,
  • Zhaoyang Jia,
  • Joey Estabrook,
  • Jen Hauenstein,
  • Neil Miller,
  • Naz Güleray-Lafci,
  • Jürgen Neesen,
  • Alex Hastie,
  • Andy Wing Chun Pang,
  • Paul Dremsek,
  • Vineet Bafna

摘要

The whole genome karyotype represents the sequence of large chromosomal segments that define an individual’s genotype, encompassing variants such as aneuploidies, balanced, and unbalanced translocations. Karyotype analysis is essential for identifying genetic risk factors, guiding diagnoses, and informing treatment and genetic counseling for constitutional disorders. Optical Genome Mapping (OGM) offers a high-resolution alternative to traditional microscopic karyotyping. We present OMKar, an automated tool that leverages OGM data to generate virtual karyotypes by processing structural variants (SVs) and copy number variants (CNVs) into a breakpoint graph. OMKar employs Integer Linear Programming to ensure chromosomal balance and identifies Eulerian paths to reconstruct chromosomes. In simulation tests, OMKar reconstruction achieved 88% precision and 95% recall for SV concordance and a 95% Jaccard score for CNV concordance. It was further validated on 154 clinical samples from ten different sites, where it successfully reconstructed 144 of the 154 karyotypes. OMKar identified genetic mechanisms for five disorders missed by traditional karyotyping, demonstrating its robustness in detecting constitutional disorders. The tool is publicly available at https://github.com/siavashre/OMKar .