title: A synonymous splicing mutation in the SF3B4 gene segregates in a family with highly variable Nager syndrome.
abstract: Nager syndrome is a rare preaxial acrofacial dysostosis that is caused by heterozygous loss-of-function variants in SF3B4. This gene encodes for a protein required for the assembly of spliceosomal complexes, being a master gene for splicing regulation. The main clinical features of Nager syndrome include facial-mandibular and preaxial limb malformations, with normal cognitive functioning. Most Nager patients are sporadic, but few familial cases with a highly variable phenotype have been reported. In this work, we report a novel synonymous variant within exon 3 of the SF3B4 gene in a family with three members affected by Nager syndrome. No pathogenic variants have been detected in other 24 genes associated with syndromes characterized by mandibulo-facial anomalies. The pathogenicity of the mutation was demonstrated through a hybrid minigene assay, which confirmed an aberrant splicing with the creation of a cryptic splice site, and showed that this allele is hypomorphic. Our findings emphasize the importance to perform functional analyses to assess the possible consequences of synonymous variants and confirmed that hybrid minigenes represent an effective tool to evaluate the effects of variants on splicing, particularly when RNA is not available.
authors.affiliation: Department of Woman and Child Health, Clinical Genetics Unit, University of Padova, Padova, Italy.|Istituto di Ricerca Pediatrica, Città della Speranza, Laboratorio di Genetica Clinica ed Epidemiologica, Padova, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Cassina
authors.affiliation: Department of Woman and Child Health, Clinical Genetics Unit, University of Padova, Padova, Italy.|Istituto di Ricerca Pediatrica, Città della Speranza, Laboratorio di Genetica Clinica ed Epidemiologica, Padova, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cerqua
authors.affiliation: Department of Woman and Child Health, Clinical Genetics Unit, University of Padova, Padova, Italy.|Istituto di Ricerca Pediatrica, Città della Speranza, Laboratorio di Genetica Clinica ed Epidemiologica, Padova, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rossi
authors.affiliation: Department of Woman and Child Health, Clinical Genetics Unit, University of Padova, Padova, Italy.|Istituto di Ricerca Pediatrica, Città della Speranza, Laboratorio di Genetica Clinica ed Epidemiologica, Padova, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salviati
authors.affiliation: Department of Neurosciences, Operative Unit of Otolaryngology and Otosurgery, University of Padova, Padova, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Martini
authors.affiliation: Department of Woman and Child Health, Clinical Genetics Unit, University of Padova, Padova, Italy.|Istituto di Ricerca Pediatrica, Città della Speranza, Laboratorio di Genetica Clinica ed Epidemiologica, Padova, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Clementi
authors.affiliation: Department of Woman and Child Health, Clinical Genetics Unit, University of Padova, Padova, Italy.|Istituto di Ricerca Pediatrica, Città della Speranza, Laboratorio di Genetica Clinica ed Epidemiologica, Padova, Italy.
authors.forename: Eva
authors.initials: E
authors.lastname: Trevisson
mesh_terms: D000328:Adult; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D008342:Mandibulofacial Dysostosis / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D012326:RNA Splicing; D000072260:RNA Splicing Factors / Q000235:genetics*
chemical_list: D000072260:RNA Splicing Factors; C486347:SF3B4 protein, human