SOX9 – Isolated Pierre Robin Sequence

Heterozygous noncoding rearrangements upstream of SOX9 cause isolated Pierre Robin sequence (PRS) via long-range enhancer disruption. A male patient with PRS and mild scapular hypoplasia harbored a paracentric inversion on 17q with a microdeletion from –4.15 Mb to –1.16 Mb relative to SOX9, implicating enhancers >1.16 Mb from the coding exons in mandibular development (PMID:22529047). In a three-generation pedigree segregating dominant PRS and subtle appendicular and axial anomalies, a ∼1 Mb deletion upstream of SOX9 (including KCNJ2/KCNJ16) co-segregated with the phenotype, refining the critical regulatory interval for PRS-plus features (PMID:26663529).

Targeted sequencing of conserved noncoding elements upstream of SOX9 in 141 nonsyndromic PRS patients identified only a single inherited variant in a GATA1‐binding site, suggesting that sequence variants in these enhancers are rare contributors to PRS (PMID:27920635). Collectively, these studies delineate a dominant regulatory mechanism whereby disruption of SOX9 upstream enhancers leads to isolated PRS without coding‐sequence mutations.

References

• American Journal of Medical Genetics Part A • 2012 • Complex genomic rearrangement in the SOX9 5' region in a patient with Pierre Robin sequence and hypoplastic left scapula PMID:22529047
• Birth Defects Research Part A • 2016 • Variability in a three-generation family with Pierre Robin sequence, acampomelic campomelic dysplasia, and intellectual disability due to a novel ~1 Mb deletion upstream of SOX9, and including KCNJ2 and KCNJ16 PMID:26663529
• Molecular Syndromology • 2016 • Clinical and Molecular Characterisation of Children with Pierre Robin Sequence and Additional Anomalies PMID:27920635

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