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Nager syndrome: confirmation of SF3B4 haploinsufficiency as the major cause |
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| Authors: | F. Petit F. Escande A.S. Jourdain N. Porchet J. Amiel B. Doray M.A. Delrue E. Flori C.A. Kim S. Marlin S.P. Robertson S. Manouvrier‐Hanu M. Holder‐Espinasse |
| Affiliation: | 1. Service de Génétique Clinique, H?pital Jeanne de Flandre, CHRU Lille, , Lille, France;2. Laboratoire de Biologie Moléculaire, Centre de Biologie Pathologie, CHRU Lille, , Lille, France;3. Université Lille Nord de France;4. Département de Génétique, H?pital Necker‐Enfants Malades, AP‐HP, , Paris, France;5. Unité INSERM U781, Faculté Paris‐Descartes, Institut IMAGINE, , Paris, France;6. Service de génétique médicale, H?pital de Hautepierre, CHU Strasbourg, , Strasbourg, France;7. Service de génétique médicale, H?pital Pellegrin, CHU Bordeaux, , Bordeaux, France;8. Instituto da Crianca, Faculdade de Medicina da Universidade de S?o Paulo, , S?o Paulo, Brazil;9. Centre de référence des surdités génétiques, service de génétique médicale, H?pital Armand Trousseau, APHP, , Paris, France;10. Clinical Genetics Laboratory, Department of Paediatrics and Child Health, University of Otago, , Otago, New Zealand;11. Clinical Genetics Department, Guy's Hospital, , London, UK |
| Abstract: | Nager syndrome belongs to the group of acrofacial dysostosis, which are characterized by the association of craniofacial and limb malformations. Recently, exome sequencing studies identified the SF3B4 gene as the cause of this condition in most patients. SF3B4 encodes a highly conserved protein implicated in mRNA splicing and bone morphogenic protein (BMP) signaling. We performed SF3B4 sequencing in 14 families (18 patients) whose features were suggestive of Nager syndrome and found nine mutations predicted to result in loss‐of‐function. SF3B4 is the major gene responsible for autosomal dominant Nager syndrome. All mutations reported predict null alleles, therefore precluding genotype–phenotype correlations. Most mutation‐negative patients were phenotypically indistinguishable from patients with mutations, suggesting genetic heterogeneity. |
| Keywords: | acro‐facial dysostosis Nager syndrome SF3B4 spliceosome |