The clinical impact of chromosomal rearrangements with breakpoints upstream of the SOX9gene: two novel de novo balanced translocations associated with acampomelic campomelic dysplasia

Abstract

BackgroundThe association of balanced rearrangements with breakpoints near SOX9 [SRY (sex determining region Y)-box 9] with skeletal abnormalities has been ascribed to the presumptive altering of SOX9 expression by the direct disruption of regulatory elements, their separation from SOX9 or the effect of juxtaposed sequences.Case presentationWe report on two sporadic apparently balanced translocations, t(7;17)(p13;q24) and t(17;20)(q24.3;q11.2), whose carriers have skeletal abnormalities that led to the diagnosis of acampomelic campomelic dysplasia (ACD; MIM 114290). No pathogenic chromosomal imbalances were detected by a-CGH. The chromosome 17 breakpoints were mapped, respectively, 917–855 kb and 601–585 kb upstream of the SOX9 gene. A distal cluster of balanced rearrangements breakpoints on chromosome 17 associated with SOX9-related skeletal disorders has been mapped to a segment 932–789 kb upstream of SOX9. In this cluster, the breakpoint of the herein described t(17;20) is the most telomeric to SOX9, thus allowing the redefining of the telomeric boundary of the distal breakpoint cluster region related to skeletal disorders to 601–585 kb upstream of SOX9. Although both patients have skeletal abnormalities, the t(7;17) carrier presents with relatively mild clinical features, whereas the t(17;20) was detected in a boy with severe broncheomalacia, depending on mechanical ventilation. Balanced and unbalanced rearrangements associated with disorders of sex determination led to the mapping of a regulatory region of SOX9 function on testicular differentiation to a 517–595 kb interval upstream of SOX9, in addition to TESCO (Testis-specific enhancer of SOX9 core). As the carrier of t(17;20) has an XY sex-chromosome constitution and normal male development for his age, the segment of chromosome 17 distal to the translocation breakpoint should contain the regulatory elements for normal testis development.ConclusionsThese two novel translocations illustrate the clinical variability in carriers of balanced translocations with breakpoints near SOX9. The translocation t(17;20) breakpoint provides further evidence for an additional testis-specific SOX9 enhancer 517 to 595 kb upstream of the SOX9 gene.

Familial 46,XY sex reversal without campomelic dysplasia caused by a deletion upstream of the SOX9 gene

“…One of the patients had a normal male phenotype and the translocation break point was located within 601 to 585 kb upstream of SOX9 gene. This eliminates another 10 kb (595-585) from the RevSex region and further narrows it down to the region 585 to 517 kb upstream of SOX9 (Figure 6) (28). In support of Benko and co-workers (23), this specific RevSex region is contained in the deletion found in the three siblings and the father described in our study.…”

Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3

“…Several deletions and translocations, mapping in the region from 585 kb to 1.8 Mb upstream of SOX9, have been reported in patients with isolated PRS. 11,29,31,32,34 These cases point to the existence of SOX9-regulatory elements, driving the expression of this gene in craniofacial structures, although no single element specifically impaired by the reported rearrangements has been yet identified.…”

“…Breakpoint mapping allowed us to precisely define the 17q breakpoint of the t(11;17) translocation, which is located~115 kb upstream of that reported by Refai et al 15 The existence of a single gonadal-specific regulatory element interrupted by both these translocations is contradicted by the presence of translocation breakpoints in the same interval in at least three unrelated 46,XX females with normal sexual development (light green in Figure 3). [31][32][33] As suggested, 31 the chromatin environment of the recipient region may alter SOX9 regulation, even though in all these cases RevSex is translocated to the derivative chromosome together with SOX9, thus, in theory, retaining the cis-regulatory elements necessary for its gonadal expression. Our patient 3 also shows signs of PRS.…”

Combinatorial CRISPR/Cas9 Approach to Elucidate a Far-Upstream Enhancer Complex for Tissue-Specific Sox9 Expression

“…CD is a severe congenital disease and a form of skeletal dysplasia that is characterized by the bowing and shortening of the long bones, a bell-shaped thorax, narrow iliac wings, respiratory distress, and, often, disorders in sexual development (Foster et al, 1994; Meyer et al, 1997; Wagner et al, 1994). By contrast, ACD is not accompanied by bowed limbs and presents milder skeletal features (Fonseca et al, 2013). Consistent with these characteristics, Sox9 haploinsufficiency in mice leads to a severe phenotype that resembles CD and ACD (Bi et al, 2001).…”