title: Germline and somatic mosaicism for FGFR2 mutation in the mother of a child with Crouzon syndrome: Implications for genetic testing in "paternal age-effect" syndromes.
abstract: Crouzon syndrome is a dominantly inherited disorder characterized by craniosynostosis and facial dysostosis, caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene; it belongs to a class of disorders that mostly arise as de novo mutations and exhibit a near-exclusive paternal origin of mutation and elevated paternal age ("paternal age effect"). However, even if this is the major mode of origin of mutations in paternal age-effect disorders, germline mosaicism may also occur. Here we describe the first molecularly documented evidence of germline and somatic mosaicism for FGFR2 mutation, identified in the mother of a child with Crouzon syndrome caused by a heterozygous c.1007A>G (p.Asp336Gly) substitution. Levels of maternal somatic mosaicism for this mutation, estimated by pyrosequencing, ranged from 3.3% in hair roots to 14.1% in blood. Our observation underlines the importance of parental molecular testing for accurate genetic counseling of the risk of recurrence for Crouzon, and other paternal age-effect syndromes.
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Goriely
authors.forename: Helen
authors.initials: H
authors.lastname: Lord
authors.forename: Jasmine
authors.initials: J
authors.lastname: Lim
authors.forename: David
authors.initials: D
authors.lastname: Johnson
authors.forename: Tracy
authors.initials: T
authors.lastname: Lester
authors.forename: Helen V
authors.initials: HV
authors.lastname: Firth
authors.forename: Andrew O M
authors.initials: AO
authors.lastname: Wilkie
mesh_terms: D000328:Adult; D002648:Child; D003394:Craniofacial Dysostosis / Q000175:diagnosis / Q000235:genetics*; D003398:Craniosynostoses / Q000175:diagnosis / Q000235:genetics*; D004247:DNA / Q000032:analysis / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D009030:Mosaicism; D009035:Mothers; D010331:Paternal Age; D010375:Pedigree; D016133:Polymerase Chain Reaction; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*; D013577:Syndrome
chemical_list: D004247:DNA; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2