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Ejhg2014205.Pdf European Journal of Human Genetics (2015) 23, 907–914 & 2015 Macmillan Publishers Limited All rights reserved 1018-4813/15 www.nature.com/ejhg ARTICLE Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants Beatriz Paumard-Hernández1, Julia Berges-Soria1, Eva Barroso1,2, Carlos I Rivera-Pedroza1, Virginia Pérez-Carrizosa1, Sara Benito-Sanz1,2, Eva López-Messa1, Fernando Santos1,2, Ignacio I García-Recuero3, Ana Romance3, María Juliana Ballesta-Martínez2,4, Vanesa López-González2,4, Ángel Campos-Barros1,2, Jaime Cruz5, Encarna Guillén-Navarro2,4,6, Jaime Sánchez del Pozo5, Pablo Lapunzina1,2, Sixto García-Miñaur1,2 and Karen E Heath*,1,2 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. European Journal of Human Genetics (2015) 23, 907–914; doi:10.1038/ejhg.2014.205; published online 1 October 2014 INTRODUCTION distinctive as females and male mosaics are more affected than Craniosynostosis, the premature fusion of one or more cranial sutures, males.6,7 Mutations in TWIST1 (MIM 601622) result in haploinsuffi- affects 1 in 2000–2500 children.1 It may occur due to genetic ciency of the transcription factor TWIST1, and are associated with mutations or secondarily, due to mechanical, environmental and Saethre–Chotzen syndrome (SCS). In the early development of the hormonal factors during pregnancy. The most frequently involved coronal suture, TWIST1 is expressed in the sutural mesenchyme single suture is the sagittal suture followed by the coronal, metopic and between the proliferating osteoblasts of the frontal and parietal bone lambdoid sutures, or multiple sutures. Craniosynostosis can be edges, and overlapping with these two populations, consistent with classified into non-syndromic (isolated) or syndromic when associated roles in separating the two bone-forming tissues and with initiating with other clinical features. and maintaining transcription of FGFR2.8 Three of the genes associated with craniosynostosis encode proteins Recently, mutations in another gene,TCF12(MIM 600480), have belonging to the fibroblast growth factor receptor (FGFR) family; been identified in patients with coronal synostosis, many of which FGFR1 (MIM 136350), FGFR2 (MIM 176943) and FGFR3 (MIM were initially referred with SCS, and in whom no TWIST1 mutation 134934). The most commonly mutated gene is FGFR2, whereas the p. had been identified.9 TCF12 encodes transcription factor 12 (TCF12), Pro250Arg mutation in FGFR3 is the most frequent mutation,2 a member of the basic helix-loop-helix (bHLH) E-protein family. It is characteristic of the Muenke syndrome.3 EFNB1 (Ephrin B1, MIM expressed in many tissues, among them bone, skeletal muscle, thymus, 300035) encodes for a ligand, ephrin-B1, which binds to EphB B- and T cells, and may participate in regulating lineage-specificgene receptors and has an important role in cell adhesion and the expression through the formation of heterodimers with other bHLH development and maintenance of the nervous system.4 Mutations in E-proteins, such as TWIST1. In a study of 347 patients with this gene, located on Xq13.1, are associated with craniofrontonasal craniosynostosis, 36 TCF12 mutations were detected, the majority of dysplasia.5 The syndrome associated with mutations in EFNB1 is which resulted in exon splicing or altered the reading frame.9 1Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain; 2Centro de Investigación Biomédica en Enfermedades Raras (CIBERER), Instituto Carlos III, Madrid, Spain; 3Maxilofacial Surgery Unit, Hospital 12 de Octubre, Madrid, Spain; 4Medical Genetics Unit, Department of Pediatrics, Hospital Clínico Universitario Virgen de la Arrixaca, Madrid, Spain; 5Dysmorphology Unit, Hospital Universitario Doce de Octubre, Madrid, Spain; 6Cátedra de Genética Médica. UCAM-Universidad Católica San Antonio de Murcia, Madrid, Spain *Correspondence: Dr KE Heath, Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, Pº Castellana 261, 28046 Madrid, Spain. Tel: +34 91 207 1010 Ext.269; Fax: +34 91 207 1040; E-mail: [email protected] Received 23 April 2014; revised 26 August 2014; accepted 29 August 2014; published online 1 October 2014 Mutation spectrum in craniosynostosis B Paumard-Hernández et al 908 More recently, a patient with coronal craniosynostosis and intellectual high incidence of mosaicism,6 all samples were analysed for this gene by HRM disability was found to have a complex balanced maternal chromo- and sequencing. The sequences and PCR conditions for FGFR1, FGFR2, somal rearrangement combining the reciprocal translocation of the FGFR3, TWIST1 and EFNB1 are shown in Supplementary Table 1, for TCF12 ERF region and an insertion which resulted in the deletion of TCF12.10 (Supplementary Table 2) and for (Supplementary Table 3). Any abnormal fi Another gene recently implicated in craniosynostosis, ERF (MIM HRM pro le was subsequently sequenced using the Big-Dye Terminator v3.1 kit (Applied Biosystems, Foster City, CA, USA) on an ABI3730XL DNA 611888), encodes for the transcription factor ERF (Ets2 repressor ERF fi Sequencer (Applied Biosystems, Carlsbad, CA, USA). The results were analysed factor). Mutations in were identi ed in 12/411 patients with a using Sequencher v5.10 (Gene Codes Corporation, Ann Arbour, MI, USA). 11 complex form of craniosynostosis. MLPA (Multiplex Ligation-dependant Probe Amplification) P080B1 (MRC Phenotypic variability in craniosynostosis makes the clinical diag- Holland, The Netherlands) was used to detect copy number alterations. nosis difficult; thus, genetic testing can support or aid the clinical diagnosis and improve genetic counselling in these families. Evidence Pathogenicity assessment also suggests that molecular diagnosis can help to define the treatment The pathogenicity of the detected alterations was assessed by determining: (1) If or surgery necessary in the short to medium term and predict the the mutation had been previously reported; (2) If not, the variations were clinical evolution.12,13 Patients with an identified TWIST1 mutation assessed using the programs Ensembl and NCBI dbSNP to determine if the have a high rate of reoperation due to intracranial hypertension,12 alteration has been described as a polymorphism. Allelic frequencies were whereas mutations in TCF12 do not.9 Thus, the knowledge of the obtained using NHLBI Exome Sequencing Project (ESP) Exome Variant Server genetic mutation permits greater monitoring of the intracranial (EVS) and the 1000 genomes, and where necessary in 300 Spanish healthy controls; (3) Amino acid conservation analysis; (4) Prediction of the function hypertension in these patients. Likewise, other studies have confirmed and pathogenicity using the bioinformatics package, Alamut 2.4.1 which that the frequency of transcranial surgery performed to reduce includes PolyPhen, SIFT, MutationTaster and various splicing predictor tools intracranial pressure is much higher in patients with Muenke (Human Splicing Finder (HSF), MaxEntScan, Splice Site Finder (SSF), 14 syndrome. It is also important to check for hearing loss in patients GeneSplicer, Splice Site Prediction by Neural Network (NNsplice); (5) with Muenke, as it has been reported that 20% require hearing aids.15 Functional analysis of splicing variants using minigene assays. In 2010, Wilkie et al,2 presented a prospective cohort of 326 patients All variants and individuals have been submitted to the gene variant database with craniosynostosis, where the molecular aetiology was identified in at www.LOVD.nl/CAV3. 84, 86% of the mutations were monogenic alterations, whereas 14% were chromosomal abnormalities. The employed molecular screening Minigenes assay for TCF12 splicing variants strategy was a two-tier cascade screening protocol, including the Minigene constructions based on the pSPL3 exon trapping vector (kind analysis of various exons of FGFR1, FGFR2, FGFR3, TWIST1 and donation from Dr
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