title: Rubinstein-Taybi syndrome type 2: report of nine new cases that extend the phenotypic and genotypic spectrum.
abstract: Rubinstein-Taybi syndrome (RTS) is an autosomal dominant neurodevelopmental disorder characterized by growth deficiency, broad thumbs and great toes, intellectual disability and characteristic craniofacial appearance. Mutations in CREBBP account for around 55% of cases, with a further 8% attributed to the paralogous gene EP300. Comparatively few reports exist describing the phenotype of Rubinstein-Taybi because of EP300 mutations. Clinical and genetic data were obtained from nine patients from the UK and Ireland with pathogenic EP300 mutations, identified either by targeted testing or by exome sequencing. All patients had mild or moderate intellectual impairment. Behavioural or social difficulties were noted in eight patients, including three with autistic spectrum disorders. Typical dysmorphic features of Rubinstein-Taybi were only variably present. Additional observations include maternal pre-eclampsia (2/9), syndactyly (3/9), feeding or swallowing issues (3/9), delayed bone age (2/9) and scoliosis (2/9). Six patients had truncating mutations in EP300, with pathogenic missense mutations identified in the remaining three. The findings support previous observations that microcephaly, maternal pre-eclampsia, mild growth restriction and a mild to moderate intellectual disability are key pointers to the diagnosis of EP300-related RTS. Variability in the presence of typical facial features of Rubinstein-Taybi further highlights clinical heterogeneity, particularly among patients identified by exome sequencing. Features that overlap with Floating-Harbor syndrome, including craniofacial dysmorphism and delayed osseous maturation, were observed in three patients. Previous reports have only described mutations predicted to cause haploinsufficiency of EP300, whereas this cohort includes the first described pathogenic missense mutations in EP300.
authors.affiliation: aDepartment of Clinical Genetics, Nottingham City Hospital, Nottingham bDepartment of Clinical Genetics, University Hospitals Bristol, Bristol cClinical Genetics Service dViapath Analytics LLP, Guy's and St Thomas' Hospital eClinical Genetics Unit, Great Ormond Street Hospital for Children, London fWest of Scotland Clinical Genetics Service, Queen Elizabeth University Hospital, Glasgow gYorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds hWellcome Trust Sanger Institute, Hinxton, Cambridge, UK iDepartment of Clinical Genetics, Our Lady's Hospital for Children jACoRD, University College Dublin, Dublin, Ireland.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Hamilton
authors.forename: Ruth
authors.initials: R
authors.lastname: Newbury-Ecob
authors.forename: Muriel
authors.initials: M
authors.lastname: Holder-Espinasse
authors.forename: Shu
authors.initials: S
authors.lastname: Yau
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lillis
authors.forename: Jane A
authors.initials: JA
authors.lastname: Hurst
authors.forename: Emma
authors.initials: E
authors.lastname: Clement
authors.forename: William
authors.initials: W
authors.lastname: Reardon
authors.forename: Shelagh
authors.initials: S
authors.lastname: Joss
authors.forename: Emma
authors.initials: E
authors.lastname: Hobson
authors.forename: Moira
authors.initials: M
authors.lastname: Blyth
authors.forename: Maryam
authors.initials: M
authors.lastname: Al-Shehhi
authors.forename: Sally A
authors.initials: SA
authors.lastname: Lynch
authors.forename: Mohnish
authors.initials: M
authors.lastname: Suri
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D050882:CREB-Binding Protein / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D050881:E1A-Associated p300 Protein / Q000235:genetics; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D012415:Rubinstein-Taybi Syndrome / Q000175:diagnosis* / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D050882:CREB-Binding Protein; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human