Fig. 2

Delineation of a balanced translocation (t(14;18)) disrupting transcription factor 4 (TCF4) using whole genome sequencing of patient DNA. (a) Ideogram depicting the patient’s apparently balanced translocation t(14,18)(q23.2;q21.2) and normal karyotype (46, XY). The ideogram of chromosome 18 is shaded in light blue color. (b) Inter-chromosome (red; chr18-chr14) and intra-chromosome (blue; chr18-chr18) connections identified by whole-genome sequence analysis. Intra-chromosomal inversion (943,387 bases) on chr18 encompasses RAB27B, and CCDC68 and interrupted DYNAP and TCF4. The inversion junctions are flanked by heterozygous deletions within TCF4 (19,394 bases (a)) and include the promoter and first exon of DYNAP transcript NM_173629 (38,926 bases (b)). Inter-chromosome connection on chr14 disrupts PLEKHG3 resulting in a 29 bp heterozygous deletion (c). Blue and orange arrows indicate genes on the positive and negative strand respectively. Dark blue and green wiggles indicate read depth via whole-genome sequencing, and segmental duplications (hg19 UCSC Human genome browser) respectively. (c) Schematic representation mechanism of the three ds-DNA breaks and genomic reorganization steps that led to the translocation event between chromosome 14 and 18. The three main steps were: (1) a 0.94 Mb inversion (blue arch, breakpoints a and b) on chromosome 18, followed by (2) ligation of the centromeric portion of chromosome 14 (red line, breakpoints c and a) with the telomeric q arm of chromosome 18 to yield der (14), and (3) ligation of the centromeric portion of chromosome 18 (red line, breakpoints c and b) ligation with the telomeric q arm of chromosome 14 to yield der (18). The schematic representation of chromosomes is not to scale. The der (14) chromosome harbors a gene fusion of PLEKHG3 (5’ untranslated region) and TCF4 (coding exons) as well as interrupted TCF4 transcript variants. The der (18) chromosome harbors a disrupted copy of PLEKHG3; the coding potential of the gene remains intact although the promoter and first non-coding exon are removed by the translocation