title: Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome.
abstract: Nager syndrome, first described more than 60 years ago, is the archetype of a class of disorders called the acrofacial dysostoses, which are characterized by craniofacial and limb malformations. Despite intensive efforts, no gene for Nager syndrome has yet been identified. In an international collaboration, FORGE Canada and the National Institutes of Health Centers for Mendelian Genomics used exome sequencing as a discovery tool and found that mutations in SF3B4, a component of the U2 pre-mRNA spliceosomal complex, cause Nager syndrome. After Sanger sequencing of SF3B4 in a validation cohort, 20 of 35 (57%) families affected by Nager syndrome had 1 of 18 different mutations, nearly all of which were frameshifts. These results suggest that most cases of Nager syndrome are caused by haploinsufficiency of SF3B4. Our findings add Nager syndrome to a growing list of disorders caused by mutations in genes that encode major components of the spliceosome and also highlight the synergistic potential of international collaboration when exome sequencing is applied in the search for genes responsible for rare Mendelian phenotypes.
authors.affiliation: Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada. francois.bernier@albertahealthservices.ca
authors.forename: Francois P
authors.initials: FP
authors.lastname: Bernier
authors.forename: Oana
authors.initials: O
authors.lastname: Caluseriu
authors.forename: Sarah
authors.initials: S
authors.lastname: Ng
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.forename: Kati J
authors.initials: KJ
authors.lastname: Buckingham
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
authors.forename: Ethylin Wang
authors.initials: EW
authors.lastname: Jabs
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Innis
authors.forename: Jane L
authors.initials: JL
authors.lastname: Schuette
authors.forename: Jerome L
authors.initials: JL
authors.lastname: Gorski
authors.forename: Peter H
authors.initials: PH
authors.lastname: Byers
authors.forename: Gregor
authors.initials: G
authors.lastname: Andelfinger
authors.forename: Victoria
authors.initials: V
authors.lastname: Siu
authors.forename: Julie
authors.initials: J
authors.lastname: Lauzon
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Fernandez
authors.forename: Margaret
authors.initials: M
authors.lastname: McMillin
authors.forename: Richard H
authors.initials: RH
authors.lastname: Scott
authors.forename: Hilary
authors.initials: H
authors.lastname: Racher
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.forename: Jillian S
authors.initials: JS
authors.lastname: Parboosingh
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D059472:Exome; D005260:Female; D057895:Haploinsufficiency; D006801:Humans; D017880:Limb Deformities, Congenital / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008342:Mandibulofacial Dysostosis / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D012322:RNA Precursors / Q000235:genetics* / Q000378:metabolism; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D017381:Spliceosomes / Q000235:genetics*; D055815:Young Adult
chemical_list: D012322:RNA Precursors; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; C486347:SF3B4 protein, human