title: Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome.
abstract: Crouzon syndrome and Pfeiffer syndrome are both autosomal dominant craniosynostotic disorders that can be caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. To determine the parental origin of these FGFR2 mutations, the amplification refractory mutation system (ARMS) was used. ARMS PCR primers were developed to recognize polymorphisms that could distinguish maternal and paternal alleles. A total of 4,374 bases between introns IIIa and 11 of the FGFR2 gene were sequenced and were assayed by heteroduplex analysis, to identify polymorphisms. Two polymorphisms (1333TA/TATA and 2710 C/T) were found and were used with two previously described polymorphisms, to screen a total of 41 families. Twenty-two of these families were shown to be informative (11 for Crouzon syndrome and 11 for Pfeiffer syndrome). Eleven different mutations in the 22 families were detected by either restriction digest or allele-specific oligonucleotide hybridization of ARMS PCR products. We molecularly proved the origin of these different mutations to be paternal for all informative cases analyzed (P=2. 4x10-7; 95% confidence limits 87%-100%). Advanced paternal age was noted for the fathers of patients with Crouzon syndrome or Pfeiffer syndrome, compared with the fathers of control individuals (34. 50+/-7.65 years vs. 30.45+/-1.28 years, P<.01). Our data on advanced paternal age corroborates and extends previous clinical evidence based on statistical analyses as well as additional reports of advanced paternal age associated with paternal origin of three sporadic mutations causing Apert syndrome (FGFR2) and achondroplasia (FGFR3). Our results suggest that older men either have accumulated or are more susceptible to a variety of germline mutations.
authors.affiliation: Department of Pediatrics, Center for Craniofacial Development and Disorders, McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Glaser
authors.forename: W
authors.initials: W
authors.lastname: Jiang
authors.forename: S A
authors.initials: SA
authors.lastname: Boyadjiev
authors.forename: A K
authors.initials: AK
authors.lastname: Tran
authors.forename: A A
authors.initials: AA
authors.lastname: Zachary
authors.forename: L
authors.initials: L
authors.lastname: Van Maldergem
authors.forename: D
authors.initials: D
authors.lastname: Johnson
authors.forename: S
authors.initials: S
authors.lastname: Walsh
authors.forename: M
authors.initials: M
authors.lastname: Oldridge
authors.forename: S A
authors.initials: SA
authors.lastname: Wall
authors.forename: A O
authors.initials: AO
authors.lastname: Wilkie
authors.forename: E W
authors.initials: EW
authors.lastname: Jabs
mesh_terms: D000168:Acrocephalosyndactylia / Q000235:genetics*; D000328:Adult; D000375:Aging / Q000235:genetics; D000483:Alleles; D003394:Craniofacial Dysostosis / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005220:Fathers; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics*; D020180:Heteroduplex Analysis; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009035:Mothers; D010375:Pedigree; D011110:Polymorphism, Genetic / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*
chemical_list: D017468:Receptors, Fibroblast Growth Factor; C496353:FGFR2 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2