[Cis-ruptions of highly conserved non-coding genomic elements distant from the SOX9 gene in the Pierre Robin...

Major developmental genes, exhibiting complex expression patterns, are often embedded within a genic desert particularly rich in regions, which though non-coding are highly conserved. The developmental expression of these genes in many areas requires coordinated regulation in time and space, which is orchestrated by some of these conserved non-coding regions, acting as transcriptional regulators. SOX9 is an essential gene for many developmental processes, such as chondrogenesis, migration and differentiation of neural crest cells and testis development. In agreement with these major expression areas, SOX9 haploinsufficiency, linked to alterations in coding sequence, leads to a polymorphic malformation syndrome - campomelic dysplasia - whose major symptoms are a bone anomaly, a Pierre Robin sequence, and a sexual differentiation anomaly (Disorder of Sex Development, DSD). SOX9 is located in a  ~2.5 Mb gene desert extremely rich in conserved sequences. We have used the SOX9 locus and campomelic dysplasia as a model to show that one or several endophenotypes within a complex syndrome may arise from a tissue-specific deregulation of a major developmental gene transcription. Our work has focused on one of these endophenotypes, SPR, characterized by the triad micro- and/or retrognathy, glossoptosis and cleft palate. Here we report in detail how we identified alterations (translocations, deletions, point mutations) in non-coding regions, located far away (more than 1.2 Mb) upstream and downstream of SOX9, in clustered or sporadic SPR cases.