Utility of Optical Genome Mapping for Accurate Detection and Fine-Mapping of Structural Variants in Elusive Rare Diseases

Abstract

Rare diseases (RDs) often have a genetic basis, yet conventional diagnostic techniques fail to identify causative genetic variations in up to 50% of cases. Structural variants (SVs), including balanced rearrangements, frequently evade detection by karyotyping, microarray, and exome sequencing. The present study utilized optical genome mapping (OGM) to investigate two patients with RDs whose genetic etiology remained unresolved despite prior genomic analyses. Patient 1 exhibited a balanced reciprocal translocation disrupting the BCL11A gene, associated with Dias-Logan syndrome. Patient 2 had a mosaic 682 kb deletion near the IHH gene, causing ectopic enhancer-promoter interactions and polydactyly, mirroring phenotypes observed in mouse models and similar human cases. These findings highlight OGM's efficacy in identifying complex SVs and underline novel pathogenic mechanisms in rare genetic disorders. Consequently, the incorporation of OGM into routine diagnostic procedures will enhance genetic diagnosis, discover new syndromes of currently unknown cause, and eventually improve the clinical management of numerous patients with rare diseases.

Keywords: BCL11A; IHH; balanced translocation; congenital malformations; enhancer–promoter interactions; optical genome mapping; structural variants.

Figure 1

Genetic analyses performed on Patient 1. (a) G-banding karyotyping and optical genome mapping results. The ideograms next to chromosomes 2 and 11 indicate the location of two breakpoints: those initially proposed from the G-banding sequence t(2;11)(p11.2;p13) and those confirmed as the true breakpoints by optical genome mapping t(2;11)(p16.1;p15.4). (b) Circus plot shows a pink line connecting chromosome 2 and chromosome 11, which represents the balanced translocation between them. (c) The genome map view illustrates the balanced translocation (ogm[GRCh38]t(2;11)(p16.1;p15.4)(60494146;3362963)). The breakpoint on chromosome 2 is located within the BCL11A gene.

Figure 2

Genetic analyses performed on Patient 2. (a) Optical genome mapping results. The genome map view shows a heterozygous 682,108 bp deletion overlapping 30 genes, with the nearest non-overlap gene being IHH (ogm[GRCh38] 2q35(219132322_219826404)x1). The allele frequency of 0.27 suggests a mosaic condition. (b) Results from the high-resolution genomic array (Affymetrix CytoScan HD SNP array). Image of chromosome 2 shows only a slight decrease in probes in the deletion region, without reaching significant values. (c) Hi-C data from Rao et al. [9] (GM12878 cell line, 10 kb resolution). This region encompasses several topologically associated domains (TADs), with the predicted TAD unions marked by blue arrows. The horizontal black bar at the bottom represents the deleted region in Patient 2, showing that this deletion could eliminate one of the TAD junctions or insulators in that region. The image was obtained from the UCSC Genome Browser on Human (GRCh37/hg19) with a converted genomic coordinate (chr2:219997044-220691125). (d) Genomic overview of the deleted region on chromosome 2q35 shows the genomic regions affected in other published cases with a similar phenotype [10,11,12]. The red bars represent deletions, and the blue bar represents duplication. The vertical dashed line indicates the 5′ end of the IHH gene, showing that only the duplication described by Yuksel-Apak [10] directly affects the IHH gene, while the deletions have breakpoints that impact different regions of the NHEJ1 gene, located distally but very close to IHH.