Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type

Abstract

Our data indicate that the distinct deletion 6p22.3 is associated with mesomelic dysplasia Savarirayan type featuring hypoplastic, triangular-shaped tibiae and abnormally shaped or hypoplastic fibulae.

New insights into the generation and role of de novo mutations in health and disease

“…The study of de novo mutations will shift more and more towards the detection and characterization of non-coding de novo mutations in disease. Although a phenomenal challenge that will require large-study cohorts and detailed functional validation, the limited number of de novo mutations per genome reduces the search space for pathogenic non-coding mutations, as was shown recently for non-coding de novo CNVs [198]. …”

Copy number variants analysis in a cohort of isolated and syndromic developmental delay/intellectual disability reveals novel genomic disorders, position effects and candidate disease genes

“…Three unrelated cases with 2 Mb overlapping de novo 6p22.3 microdeletions spanning 4 genes with no previous association with skeletal anomalies were identified. 40 The discovery of a fourth individual with a larger deletion but no skeletal phenotype, as well as the identification of 2 TAD boundaries in the interval, suggest that the deletion might cause the aberrant activation of potential limb enhancers in the region. 40 In a second case, we found the deletion of a TAD boundary in proximity of CTNND2 (Figure 4).…”

“…40 The discovery of a fourth individual with a larger deletion but no skeletal phenotype, as well as the identification of 2 TAD boundaries in the interval, suggest that the deletion might cause the aberrant activation of potential limb enhancers in the region. 40 In a second case, we found the deletion of a TAD boundary in proximity of CTNND2 (Figure 4). We propose that the deletion may cause altered expression of the encoded protein, δ-catenin, a regulator of synaptogenesis and dendritic morphogenesis cooperating with Erbin.…”

Deletion of the transcription factor SOX4 is implicated in syndromic nephroblastoma

“…4Four patients with 6p22.3 microdeletion encompassing SOX4 have been described, with 3 of them having an autosomal dominant mesomelic dysplasia Savarirayan type. 5 The authors supposed that the physiopathologic mechanism was the deletion of a topologically associated domain (TAD), with ectopic interactions between enhancers and the ID4 gene.In our patient, this deletion only encompasses the boundary between 2 TADs (Figure 1(a)), and it could therefore impact the regulation of the expression of E2F3, a well-known oncogene, implicated in the p53 pathway. To conclude, we suspect the deletion of SOX4 and the potential dysregulation of E2F3 to be part of a tumorogenesis process, leading to the occurrence of a nephroblastoma in our patient.…”

“…4 Four patients with 6p22.3 microdeletion encompassing SOX4 have been described, with 3 of them having an autosomal dominant mesomelic dysplasia Savarirayan type. 5 The authors supposed that the physiopathologic mechanism was the deletion of a topologically associated domain (TAD), with ectopic interactions between enhancers and the ID4 gene.…”