title: Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants.
abstract: Craniosynostosis, caused by the premature fusion of one or more of the cranial sutures, can be classified into non-syndromic or syndromic and by which sutures are affected. Clinical assignment is a difficult challenge due to the high phenotypic variability observed between syndromes. During routine diagnostics, we screened 182 Spanish craniosynostosis probands, implementing a four-tiered cascade screening of FGFR2, FGFR3, FGFR1, TWIST1 and EFNB1. A total of 43 variants, eight novel, were identified in 113 (62%) patients: 104 (92%) detected in level 1; eight (7%) in level 2 and one (1%) in level 3. We subsequently screened additional genes in the probands with no detected mutation: one duplication of the IHH regulatory region was identified in a patient with craniosynostosis Philadelphia type and five variants, four novel, were identified in the recently described TCF12, in probands with coronal or multisuture affectation. In the 19 Saethre-Chotzen syndrome (SCS) individuals in whom a variant was detected, 15 (79%) carried a TWIST1 variant, whereas four (21%) had a TCF12 variant. Thus, we propose that TCF12 screening should be included for TWIST1 negative SCS patients and in patients where the coronal suture is affected. In summary, a molecular diagnosis was obtained in a total of 119/182 patients (65%), allowing the correct craniosynostosis syndrome classification, aiding genetic counselling and in some cases provided a better planning on how and when surgical intervention should take place and, subsequently the appropriate clinical follow up.
authors.affiliation: Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Paumard-Hernández
authors.affiliation: Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Berges-Soria
authors.affiliation: 1] Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain [2] Centro de Investigación Biomédica en Enfermedades Raras (CIBERER), Instituto Carlos III, Madrid, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Barroso
authors.affiliation: Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: Carlos I
authors.initials: CI
authors.lastname: Rivera-Pedroza
authors.affiliation: Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Pérez-Carrizosa
authors.affiliation: 1] Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain [2] Centro de Investigación Biomédica en Enfermedades Raras (CIBERER), Instituto Carlos III, Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Benito-Sanz
authors.affiliation: Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: López-Messa
authors.affiliation: 1] Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain [2] Centro de Investigación Biomédica en Enfermedades Raras (CIBERER), Instituto Carlos III, Madrid, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Santos
authors.affiliation: Maxilofacial Surgery Unit, Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Ignacio I
authors.initials: II
authors.lastname: García-Recuero
authors.affiliation: Maxilofacial Surgery Unit, Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Romance
authors.affiliation: 1] Centro de Investigación Biomédica en Enfermedades Raras (CIBERER), Instituto Carlos III, Madrid, Spain [2] Medical Genetics Unit, Department of Pediatrics, Hospital Clínico Universitario Virgen de la Arrixaca, Madrid, Spain.
authors.forename: Juliana María
authors.initials: JM
authors.lastname: Ballesta-Martínez
authors.affiliation: 1] Centro de Investigación Biomédica en Enfermedades Raras (CIBERER), Instituto Carlos III, Madrid, Spain [2] Medical Genetics Unit, Department of Pediatrics, Hospital Clínico Universitario Virgen de la Arrixaca, Madrid, Spain.
authors.forename: Vanesa
authors.initials: V
authors.lastname: López-González
authors.affiliation: 1] Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain [2] Centro de Investigación Biomédica en Enfermedades Raras (CIBERER), Instituto Carlos III, Madrid, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Campos-Barros
authors.affiliation: Dysmorphology Unit, Hospital Universitario Doce de Octubre, Madrid, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Cruz
authors.affiliation: 1] Centro de Investigación Biomédica en Enfermedades Raras (CIBERER), Instituto Carlos III, Madrid, Spain [2] Medical Genetics Unit, Department of Pediatrics, Hospital Clínico Universitario Virgen de la Arrixaca, Madrid, Spain [3] Cátedra de Genética Médica. UCAM-Universidad Católica San Antonio de Murcia, Madrid, Spain.
authors.forename: Encarna
authors.initials: E
authors.lastname: Guillén-Navarro
authors.affiliation: Dysmorphology Unit, Hospital Universitario Doce de Octubre, Madrid, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Sánchez Del Pozo
authors.affiliation: 1] Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain [2] Centro de Investigación Biomédica en Enfermedades Raras (CIBERER), Instituto Carlos III, Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Lapunzina
authors.affiliation: 1] Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain [2] Centro de Investigación Biomédica en Enfermedades Raras (CIBERER), Instituto Carlos III, Madrid, Spain.
authors.forename: Sixto
authors.initials: S
authors.lastname: García-Miñaur
authors.affiliation: 1] Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain [2] Centro de Investigación Biomédica en Enfermedades Raras (CIBERER), Instituto Carlos III, Madrid, Spain.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Heath
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D015331:Cohort Studies; D003398:Craniosynostoses / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D036387:Ephrin-B1 / Q000235:genetics; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D010375:Pedigree; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013030:Spain; D051879:Twist-Related Protein 1 / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D036387:Ephrin-B1; D009687:Nuclear Proteins; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3; D051879:Twist-Related Protein 1; C484288:EFNB1 protein, human; C103173:TWIST1 protein, human; C073366:TCF12 protein, human; C496348:FGFR1 protein, human; C496353:FGFR2 protein, human; C496365:FGFR3 protein, human