case_images: PMC11818634_01
case_images: 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.
case_images: ijms-26-01244-g001.jpg
case_images: PMC11818634_01_ijms-26-01244-g001.jpg
case_images: ijms-26-01244-f001
case_images: Peripheral blood karyotyping revealed a reciprocal translocation in the patient, which was not detected in the blood cells of either the mother or the sperm donor (46,XY,t(2;11)(p11.2;p13)dn) (Figure 1a). OGM analysis confirmed the translocation between chromosomes 2 and 11, redefining the breakpoint regions more precisely, from 46,XY,t(2;11)(p11.2;p13):as identified in Karyotyping:to 46,XY,t(2;11)(p16.1;p15.4) (Figure 1b). The sites surrounding the translocation breakpoint region are located at positions chr2:60,494,146, in the large intron 2 of the BCL11A gene, and chr11:3,362,963, in the intron 3 of the ZNF195 gene, respectively (ogm[GRCh38] t(2;11)(p16.1;p15.4)(60494146;3362963)) (Figure 1c).
case_images: PMC11818634_02
case_images: 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. (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. 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 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.
case_images: ijms-26-01244-g002.jpg
case_images: PMC11818634_02_ijms-26-01244-g002.jpg
case_images: ijms-26-01244-f002
case_images: TUBA4A, TUBA4B, DNAJB2, PTPRN, MIR153-1, RESP18, DNPEP, DNPEP-AS1, DES, SPEG, SPEGNB, GMPPA, ASIC4, CHPF, TMEM198, MIR3132, OBSL1, INHA, STK11IP, and SLC4A3) (Figure 2a). This mosaic alteration, with a variant allelic frequency of 0.27, had remained undetected in all previous genetic analysis, including genomic array studies. However, a posterior visual inspection of the region in the array confirmed a slight decrease in the signal intensity for all probes in the affected region, without reaching the threshold value established by the manufacturer for variant calling (Figure 2b).