Bionano Genomics, Inc. announced the publication of a study detailing the challenges associated with the detection and interpretation of causal variants in Mendelian disease, using a cohort of 4,577 families. The study authors conducted a comprehensive analysis of samples from the cohort in which non-sequencing-based challenges were encountered, and then reanalyzed samples using exome sequencing (ES), whole-genome sequencing (WGS), chromosomal microarray (CMA) and optical genome mapping (OGM), finding that addressing these challenges alone could boost diagnostic yield of causal variants by approximately 71% and underscoring the need for a thorough approach to undiagnosed diseases. The study authors reanalyzed and reinterpreted 314 samples with negative clinical exome or genome sequencing using a combination of traditional and novel techniques and were able to identify the likely causal variant in 54.5% of samples.

OGM was used to analyze samples that remained negative after ES and was particularly relevant in the detection of large variants that were below the limit of detection of CMA. OGM's utility was illustrated in a pedigree structure case where researchers reviewed challenges associated with imprinting disorders appearing to be autosomal recessive phenotypes. OGM was used to analyze three pediatric cases of split hand/foot malformation syndrome after karyotyping, ES and RNA sequencing all failed to identify a causal variant.

OGM revealed a tandem duplication impacting multiple genes in all three cases, indicating paternal gonadal mosaicism. In addition to this finding, the authors reported additional instances where OGM was used to resolve cases involving structural variants coming from multiple classes that were highly complex.