title: Nager syndrome: confirmation of SF3B4 haploinsufficiency as the major cause.
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.
authors.affiliation: Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHRU Lille, Lille, France; Laboratoire de Biologie Moléculaire, Centre de Biologie Pathologie, CHRU Lille, Lille, France; Université Lille Nord de France.
authors.forename: F
authors.initials: F
authors.lastname: Petit
authors.forename: F
authors.initials: F
authors.lastname: Escande
authors.forename: A S
authors.initials: AS
authors.lastname: Jourdain
authors.forename: N
authors.initials: N
authors.lastname: Porchet
authors.forename: J
authors.initials: J
authors.lastname: Amiel
authors.forename: B
authors.initials: B
authors.lastname: Doray
authors.forename: M A
authors.initials: MA
authors.lastname: Delrue
authors.forename: E
authors.initials: E
authors.lastname: Flori
authors.forename: C A
authors.initials: CA
authors.lastname: Kim
authors.forename: S
authors.initials: S
authors.lastname: Marlin
authors.forename: S P
authors.initials: SP
authors.lastname: Robertson
authors.forename: S
authors.initials: S
authors.lastname: Manouvrier-Hanu
authors.forename: M
authors.initials: M
authors.lastname: Holder-Espinasse
mesh_terms: D001483:Base Sequence; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D057895:Haploinsufficiency / Q000235:genetics*; D006801:Humans; D008297:Male; D008342:Mandibulofacial Dysostosis / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; C486347:SF3B4 protein, human
keywords: Nager syndrome; SF3B4; acro-facial dysostosis; spliceosome