Complex genomic rearrangement in the SOX9 5' region in a patient with Pierre Robin sequence and hypoplastic left scapula.

Pierre Robin sequence (PRS) can occur as a component of campomelic dysplasia (CD) and acampomelic CD (ACD) caused by dysfunction or dysregulation of SOX9, although it can also take place as an isolated form. Recently, genomic alterations in the far upstream and the far downstream region of SOX9 have been identified in patients with isolated PRS. Here, we report on a male patient with PRS and a heterozygous genomic rearrangement in the 5' region of SOX9. Clinical analysis revealed PRS-compatible craniofacial anomalies, mild hypoplasia of the left scapula, and normal male external genitalia. Molecular analysis identified a paracentric inversion on the long arm of chromosome 17 with breakpoints at 17q21.31 and 17q24.3, and a microdeletion spanning from -4.15 to -1.16 Mb relative to SOX9. These findings indicate that the chromosomal region more than 1.16 Mb apart from SOX9 contains at least one developmental enhancer(s) for SOX9 that plays a critical role in the development of the mandible and a relatively small role in the development of the scapula. Moreover, the concept of exclusion mapping argues that putative CD/ACD loci are located within the 1.16 Mb region closest to SOX9 coding exons, which remain intact in this Non-CD/ACD patient. This study provides a novel example for long-range cis-regulatory mutations of SOX9.