title: FGFR2 mutation in a patient without typical features of Pfeiffer syndrome--The emerging role of combined NGS and phenotype based strategies.
abstract: Pfeiffer syndrome (MIM: #101600) is a rare autosomal dominant disorder classically characterized by limb and craniofacial anomalies. It is caused by heterozygous mutations in the fibroblast growth factor receptors types 1 and 2 (FGFR1 and FGFR2). We applied a next generation sequencing (NGS) panel approach comprising all 2877 genes currently known to be causative for one or more Mendelian diseases combined with the phenotype based computational tool PhenIX (Phenotypic Interpretation of eXomes). We report on a patient presenting with multiple anomalies of hands and feet including brachydactyly and symphalangism. No clinical diagnosis could be established based on the clinical findings and testing of several genes associated with brachydactyly and symphalangism failed to identify mutations. Via next generation sequencing (NGS) panel approach we then identified a novel de novo missense FGFR2 mutation affecting an amino acid reported to be mutated in Pfeiffer syndrome. Since our patient shows typical radiological findings of Pfeiffer syndrome in hands and feet but at the same time lacks several characteristic features such as clinical signs of craniosynostosis and prominent eyes we suggest introducing the term "FGFR2 associated phenotypes" for similar cases. Our results highlight the emerging role of combined NGS and phenotype based bioinformatics strategies to establish clinical diagnoses.
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ricarda
authors.initials: R
authors.lastname: Flöttmann
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Alexej
authors.initials: A
authors.lastname: Knaus
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Zemojtel
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany; Max Planck Institute for Molecular Genetics, Berlin, Germany; Berlin-Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Robinson
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany; Max Planck Institute for Molecular Genetics, Berlin, Germany; Berlin-Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany; Max Planck Institute for Molecular Genetics, Berlin, Germany; Berlin-Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany. Electronic address: malte.spielmann@charite.de.
authors.forename: Malte
authors.initials: M
authors.lastname: Spielmann
mesh_terms: D000168:Acrocephalosyndactylia / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D002675:Child, Preschool; D019295:Computational Biology / Q000379:methods; D005260:Female; D050278:Finger Phalanges / Q000002:abnormalities / Q000000981:diagnostic imaging; D015870:Gene Expression; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008958:Models, Molecular; D020125:Mutation, Missense; D010641:Phenotype; D011859:Radiography; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*; D050277:Toe Phalanges / Q000002:abnormalities / Q000000981:diagnostic imaging
chemical_list: C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2
keywords: FGFR2; FGFR2 Ala172Asn mutation; Pfeiffer syndrome