title: Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis.
abstract: Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic condition characterized by ocular, cutaneous, and central nervous system anomalies. Key clinical features include a well-demarcated hairless fatty nevus on the scalp, benign ocular tumors, and central nervous system lipomas. Seizures, spasticity, and intellectual disability can be present, although affected individuals without seizures and with normal intellect have also been reported. Given the patchy and asymmetric nature of the malformations, ECCL has been hypothesized to be due to a post-zygotic, mosaic mutation. Despite phenotypic overlap with several other disorders associated with mutations in the RAS-MAPK and PI3K-AKT pathways, the molecular etiology of ECCL remains unknown. Using exome sequencing of DNA from multiple affected tissues from five unrelated individuals with ECCL, we identified two mosaic mutations, c.1638C>A (p.Asn546Lys) and c.1966A>G (p.Lys656Glu) within the tyrosine kinase domain of FGFR1, in two affected individuals each. These two residues are the most commonly mutated residues in FGFR1 in human cancers and are associated primarily with CNS tumors. Targeted resequencing of FGFR1 in multiple tissues from an independent cohort of individuals with ECCL identified one additional individual with a c.1638C>A (p.Asn546Lys) mutation in FGFR1. Functional studies of ECCL fibroblast cell lines show increased levels of phosphorylated FGFRs and phosphorylated FRS2, a direct substrate of FGFR1, as well as constitutive activation of RAS-MAPK signaling. In addition to identifying the molecular etiology of ECCL, our results support the emerging overlap between mosaic developmental disorders and tumorigenesis.
authors.affiliation: Department of Pediatrics (Genetics), University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Bennett
authors.affiliation: Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: Tiong Yang
authors.initials: TY
authors.lastname: Tan
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Brighton BN19RQ, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Alcantara
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC H3A0G4 Canada.
authors.forename: Martine
authors.initials: M
authors.lastname: Tétrault
authors.affiliation: Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Timms
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Jensen
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Collins
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4J9, Canada.
authors.forename: Malgorzata J M
authors.initials: MJM
authors.lastname: Nowaczyk
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Marjorie J
authors.initials: MJ
authors.lastname: Lindhurst
authors.affiliation: Department of Pediatrics, Cardinal Glennon Children's Medical Center, St. Louis, MO 63104, USA.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Christensen
authors.affiliation: Department of Pediatrics, Cardinal Glennon Children's Medical Center, St. Louis, MO 63104, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Braddock
authors.affiliation: Departments of Pediatrics and Medicine (Dermatology), University of Washington, Seattle, WA 98195, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Brandling-Bennett
authors.affiliation: Department of Pediatrics, Academic Medical Centre, University of Amsterdam, 1105AZ Amsterdam, Netherlands.
authors.forename: Raoul C M
authors.initials: RCM
authors.lastname: Hennekam
authors.affiliation: Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, University of Hong Kong, 21 Sassoon Road, Hong Kong, China.
authors.forename: Brian
authors.initials: B
authors.lastname: Chung
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H3N1, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Lehman
authors.affiliation: Monash University, Eastern Health, Department of Dermatology, Box Hill, VIC 3128, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Su
authors.affiliation: Monash University, Eastern Health, Department of Dermatology, Box Hill, VIC 3128, Australia.
authors.forename: SuYuen
authors.initials: S
authors.lastname: Ng
authors.affiliation: Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Amor
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC H3A0G4 Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Les G
authors.initials: LG
authors.lastname: Biesecker
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H5B2, Canada.
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.affiliation: Department of Pediatrics (Genetics), University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Neurology, University of Washington, Seattle, WA 98195, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Brighton BN19RQ, UK. Electronic address: m.o-driscoll@sussex.ac.uk.
authors.forename: Mark
authors.initials: M
authors.lastname: O'Driscoll
authors.affiliation: Institute of Human Genetics, Heidelberg University, 69120 Heidelberg, Germany. Electronic address: ute.moog@med.uni-heidelberg.de.
authors.forename: Ute
authors.initials: U
authors.lastname: Moog
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H5B2, Canada.
authors.forename: Laura M
authors.initials: LM
authors.lastname: McDonell
mesh_terms: D000293:Adolescent; D045744:Cell Line, Tumor; D016543:Central Nervous System Neoplasms / Q000175:diagnosis / Q000235:genetics; D002675:Child, Preschool; D059472:Exome; D005123:Eye / Q000503:physiopathology; D005128:Eye Diseases / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008068:Lipomatosis / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D020752:Neurocutaneous Syndromes / Q000175:diagnosis / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics* / Q000378:metabolism; D012640:Seizures / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D019869:Phosphatidylinositol 3-Kinases; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051057:Proto-Oncogene Proteins c-akt