title: Clinical and Molecular Characterisation of Children with Pierre Robin Sequence and Additional Anomalies.
abstract: Pierre Robin Sequence (PRS) is usually classified into syndromic and nonsyndromic groups, with a further subclassification of the nonsyndromic group into isolated PRS and PRS with additional anomalies (PRS-Plus). The aim of this research is to provide an accurate phenotypic characterisation of nonsyndromic PRS, specifically the PRS-Plus subgroup. We sought to examine the frequency of sequence variants in previously defined conserved noncoding elements (CNEs) in the putative enhancer region upstream ofSOX9, the regulation of which has been associated with PRS phenotypes. We identified 141 children with nonsyndromic PRS at the Royal Children's Hospital, Melbourne from 1985 to 2012 using 2 databases. Clinical and demographic data were extracted by file review and children categorized as 'isolated PRS' or 'PRS-Plus'. A subset of children with PRS-Plus was selected for detailed phenotyping and DNA sequencing of the upstreamSOX9CNEs. We found 83 children with isolated PRS and 58 with PRS-Plus. The most common PRS-Plus malformations involved the musculoskeletal and ocular systems. The most common coexisting craniofacial malformation was choanal stenosis/atresia. We identified 10 children with a family history of PRS or cleft palate. We found a single nucleotide substitution in a putativeGATA1-binding site in one patient, but it was inherited from his phenotypically unaffected mother. PRS-Plus represents a broad phenotypic spectrum with uncertain pathogenesis. Dysmorphology assessment by a clinical geneticist is recommended.SOX9CNE sequence variants are rare in our cohort and are unlikely to play a significant role in the pathogenesis of PRS-Plus.
authors.affiliation: Murdoch Childrens Research Institute, University of Melbourne, Melbourne, Vic., Australia; Department of Paediatrics, University of Melbourne, Melbourne, Vic., Australia.
authors.forename: Jessie X
authors.initials: JX
authors.lastname: Xu
authors.affiliation: Murdoch Childrens Research Institute, University of Melbourne, Melbourne, Vic., Australia; Department of Paediatrics, University of Melbourne, Melbourne, Vic., Australia; Royal Children's Hospital, Melbourne, Vic., Australia.
authors.forename: Nicky
authors.initials: N
authors.lastname: Kilpatrick
authors.affiliation: Murdoch Childrens Research Institute, University of Melbourne, Melbourne, Vic., Australia.
authors.forename: Naomi L
authors.initials: NL
authors.lastname: Baker
authors.affiliation: Murdoch Childrens Research Institute, University of Melbourne, Melbourne, Vic., Australia; Department of Paediatrics, University of Melbourne, Melbourne, Vic., Australia; Royal Children's Hospital, Melbourne, Vic., Australia.
authors.forename: Anthony
authors.initials: A
authors.lastname: Penington
authors.affiliation: Murdoch Childrens Research Institute, University of Melbourne, Melbourne, Vic., Australia; Department of Paediatrics, University of Melbourne, Melbourne, Vic., Australia.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Farlie
authors.affiliation: Murdoch Childrens Research Institute, University of Melbourne, Melbourne, Vic., Australia; Department of Paediatrics, University of Melbourne, Melbourne, Vic., Australia; Royal Children's Hospital, Melbourne, Vic., Australia; Victorian Clinical Genetics Services, Melbourne, Vic., Australia.
authors.forename: Tiong Yang
authors.initials: TY
authors.lastname: Tan
keywords: Birth defects; Craniofacial anomalies; Dysmorphology; Noncoding DNA; Phenotyping; SOX9