title: Mosaic CREBBP mutation causes overlapping clinical features of Rubinstein-Taybi and Filippi syndromes.
abstract: Rubinstein-Taybi syndrome (RTS, OMIM 180849) and Filippi syndrome (FLPIS, OMIM 272440) are both rare syndromes, with multiple congenital anomalies and intellectual deficit (MCA/ID). We present a patient with intellectual deficit, short stature, bilateral syndactyly of hands and feet, broad thumbs, ocular abnormalities, and dysmorphic facial features. These clinical features suggest both RTS and FLPIS. Initial DNA analysis of DNA isolated from blood did not identify variants to confirm either of these syndrome diagnoses. Whole-exome sequencing identified a homozygous variant in C9orf173, which was novel at the time of analysis. Further Sanger sequencing analysis of FLPIS cases tested negative for CKAP2L variants did not, however, reveal any further variants. Subsequent analysis using DNA isolated from buccal mucosa revealed a mosaic variant in CREBBP. This report highlights the importance of excluding mosaic variants in patients with a strong but atypical clinical presentation of a MCA/ID syndrome if no disease-causing variants can be detected in DNA isolated from blood samples. As the striking syndactyly observed in the present case is typical for FLPIS, we suggest CREBBP analysis in saliva samples for FLPIS syndrome cases in which no causal CKAP2L variant is detected.
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Tamar I
authors.initials: TI
authors.lastname: de Vries
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Glen R
authors.initials: GR
authors.lastname: Monroe
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Martine J
authors.initials: MJ
authors.lastname: van Belzen
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Christian A
authors.initials: CA
authors.lastname: van der Lans
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Sanne Mc
authors.initials: SM
authors.lastname: Savelberg
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester, UK.
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Gijs
authors.identifier: 0000-0003-3033-0329
authors.initials: G
authors.lastname: van Haaften
authors.affiliation: Department of Pediatric Radiology, University Medical Center Utrecht/Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors.forename: Rutger A
authors.initials: RA
authors.lastname: Nievelstein
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Mieke M
authors.identifier: 0000-0002-7519-0246
authors.initials: MM
authors.lastname: van Haelst
mesh_terms: D050882:CREB-Binding Protein / Q000235:genetics*; D002648:Child; D003598:Cytoskeletal Proteins / Q000235:genetics; D003937:Diagnosis, Differential; D019066:Facies; D005820:Genetic Testing / Q000379:methods; D006130:Growth Disorders / Q000175:diagnosis / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics*; D009030:Mosaicism; D009154:Mutation; D010641:Phenotype; D012415:Rubinstein-Taybi Syndrome / Q000175:diagnosis / Q000235:genetics*; D013576:Syndactyly / Q000175:diagnosis / Q000235:genetics*
chemical_list: C114988:CKAP2 protein, human; D003598:Cytoskeletal Proteins; D050882:CREB-Binding Protein; C494363:CREBBP protein, human