Reliable detection of robertsonian translocations via genomic proximity mapping

The National Institutes of Health National Human Genome Research Institute awarded Cytoterra Inc. $296,543 on September 1, 2026, under the Human Genome Research program (CFDA 93.172) to develop an NGS-based method for detecting Robertsonian translocations, which are whole-arm fusions between acrocentric chromosomes and among the most common large structural rearrangements in humans yet remain challenging to identify with current high-throughput genomics techniques.

The project integrates distal junction copy number analysis with genomic proximity mapping (a Hi-C-based structural variant detection approach) to overcome the detection challenge posed by the highly repetitive nature of acrocentric chromosome p-arms. The method modifies reference genomes to mask endogenous distal junction sequences and introduces an artificial distal junction contig, enabling accurate copy number estimation while maintaining compatibility with clinical-grade genome assemblies. Combined with proximity ligation data, the approach will infer both the presence and identity of fused acrocentric chromosomes, closing a gap in scalable NGS diagnostics and enhancing the clinical utility of genomic proximity mapping for cytogenetics replacement.

Performance occurs in Seattle, Washington with a period of performance from September 1, 2026, through August 31, 2027.

Abstract

Robertsonian translocations-whole-arm fusions between Q-arms of acrocentric chromosomes- are among the most common large structural rearrangements in humans, yet remain challenging to detect with current high-throughout genomics techniques. This is due to the highly repetitive nature of the acrocentric P-arms in which breakpoints occur. The proposed project aims to develop the first NGS-based method for detecting all types of robertsonian translocations by integrating distal junction (DJ) copy number analysis with genomic proximity mapping (GPM), a HI-C-based structural variant detection approach. By modifying the reference genome to mask endogenous DJ sequences and introducing a single artificial DJ contig, we will enable accurate DJ copy number estimations while preserving compatibility with clinical-grade genome assemblies. Combined with proximity ligation data, this approach will allow US to infer both the presence and identity of fused acrocentric chromosomes, overcoming a long-standing GAP in scalable NGS diagnostics. The resulting methods will enhance the clinical utility of GPM and bring US closer to a comprehensive sequencing-based replacement for traditional cytogenetics.