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A synonymous splicing mutation in the SF3B4 gene segregates in a family with highly variable Nager syndrome.
Eur J Hum Genet. 2017 02; 25(3):371-375.EJ

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+Show Affiliations

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.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.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.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.Department of Neurosciences, Operative Unit of Otolaryngology and Otosurgery, University of Padova, Padova, Italy.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.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.

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27966544

Citation

Cassina, Matteo, et al. "A Synonymous Splicing Mutation in the SF3B4 Gene Segregates in a Family With Highly Variable Nager Syndrome." European Journal of Human Genetics : EJHG, vol. 25, no. 3, 2017, pp. 371-375.
Cassina M, Cerqua C, Rossi S, et al. A synonymous splicing mutation in the SF3B4 gene segregates in a family with highly variable Nager syndrome. Eur J Hum Genet. 2017;25(3):371-375.
Cassina, M., Cerqua, C., Rossi, S., Salviati, L., Martini, A., Clementi, M., & Trevisson, E. (2017). A synonymous splicing mutation in the SF3B4 gene segregates in a family with highly variable Nager syndrome. European Journal of Human Genetics : EJHG, 25(3), 371-375. https://doi.org/10.1038/ejhg.2016.176
Cassina M, et al. A Synonymous Splicing Mutation in the SF3B4 Gene Segregates in a Family With Highly Variable Nager Syndrome. Eur J Hum Genet. 2017;25(3):371-375. PubMed PMID: 27966544.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A synonymous splicing mutation in the SF3B4 gene segregates in a family with highly variable Nager syndrome. AU - Cassina,Matteo, AU - Cerqua,Cristina, AU - Rossi,Silvia, AU - Salviati,Leonardo, AU - Martini,Alessandro, AU - Clementi,Maurizio, AU - Trevisson,Eva, Y1 - 2016/12/14/ PY - 2016/07/29/received PY - 2016/10/07/revised PY - 2016/11/01/accepted PY - 2016/12/15/pubmed PY - 2017/8/8/medline PY - 2016/12/15/entrez SP - 371 EP - 375 JF - European journal of human genetics : EJHG JO - Eur J Hum Genet VL - 25 IS - 3 N2 - 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. SN - 1476-5438 UR - https://www.unboundmedicine.com/medline/citation/27966544/A_synonymous_splicing_mutation_in_the_SF3B4_gene_segregates_in_a_family_with_highly_variable_Nager_syndrome_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/27966544/ DB - PRIME DP - Unbound Medicine ER -