title: 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.
abstract: BACKGROUND
  Campomelic dysplasia and acampomelic campomelic dysplasia (ACD) are allelic disorders due to heterozygous mutations in or around SOX9. Translocations and deletions involving the SOX9 5' regulatory region are rare causes of these disorders, as well as Pierre Robin sequence (PRS) and 46,XY gonadal dysgenesis. Genotype-phenotype correlations are not straightforward due to the complex epigenetic regulation of SOX9 expression during development.
  
  
  METHODS
  We report a three-generation pedigree with a novel ∼1 Mb deletion upstream of SOX9 and including KCNJ2 and KCNJ16, and ascertained for dominant transmission of PRS.
  
  
  RESULTS
  Further characterization of the family identified subtle appendicular anomalies and a variable constellation of axial skeletal features evocative of ACD in several members. Affected males showed learning disability.
  
  
  CONCLUSIONS
  The identified deletion was smaller than all other chromosome rearrangements associated with ACD. Comparison with other reported translocations and deletions involving this region allowed further refining of genotype-phenotype correlations and an update of the smallest regions of overlap associated with the different phenotypes. Intrafamilial variability in this pedigree suggests a phenotypic continuity between ACD and PRS in patients carrying mutations in the SOX9 5' regulatory region.
authors.affiliation: Division of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Castori
authors.affiliation: Division of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Bottillo
authors.affiliation: Division of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Morlino
authors.affiliation: Center for Genetic Counseling and Reproductive Teratology, Maternal and Child Health Department, Garibaldi Nesima Hospital, Catania, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Barone
authors.affiliation: Division of Maxillo-Facial Surgery, Sapienza University, Policlinico Umberto I Hospital, Rome, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Cascone
authors.affiliation: Division of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Grammatico
authors.affiliation: Division of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Laino
mesh_terms: D000328:Adult; D001483:Base Sequence; D055036:Campomelic Dysplasia / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D005799:Genes, Dominant; D056726:Genetic Association Studies; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D010855:Pierre Robin Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D024661:Potassium Channels, Inwardly Rectifying / Q000172:deficiency / Q000235:genetics*; D055758:SOX9 Transcription Factor / Q000235:genetics*; D017384:Sequence Deletion; D000097062:Kir5.1 Channel
chemical_list: D024661:Potassium Channels, Inwardly Rectifying; D055758:SOX9 Transcription Factor; C576242:KCNJ16 protein, human; D000097062:Kir5.1 Channel; C489457:KCNJ2 protein, human; C527932:SOX9 protein, human
keywords: Robin sequence; SOX9; acampomelic; deletion; genotype-phenotype correlations; variability