title: Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
abstract: The exon-junction complex (EJC) performs essential RNA processing tasks. Here, we describe the first human disorder, thrombocytopenia with absent radii (TAR), caused by deficiency in one of the four EJC subunits. Compound inheritance of a rare null allele and one of two low-frequency SNPs in the regulatory regions of RBM8A, encoding the Y14 subunit of EJC, causes TAR. We found that this inheritance mechanism explained 53 of 55 cases (P < 5 × 10(-228)) of the rare congenital malformation syndrome. Of the 53 cases with this inheritance pattern, 51 carried a submicroscopic deletion of 1q21.1 that has previously been associated with TAR, and two carried a truncation or frameshift null mutation in RBM8A. We show that the two regulatory SNPs result in diminished RBM8A transcription in vitro and that Y14 expression is reduced in platelets from individuals with TAR. Our data implicate Y14 insufficiency and, presumably, an EJC defect as the cause of TAR syndrome.
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, UK. caa@sanger.ac.uk
authors.forename: Cornelis A
authors.initials: CA
authors.lastname: Albers
authors.forename: Dirk S
authors.initials: DS
authors.lastname: Paul
authors.forename: Harald
authors.initials: H
authors.lastname: Schulze
authors.forename: Kathleen
authors.initials: K
authors.lastname: Freson
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Stephens
authors.forename: Peter A
authors.initials: PA
authors.lastname: Smethurst
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Jolley
authors.forename: Ana
authors.initials: A
authors.lastname: Cvejic
authors.forename: Myrto
authors.initials: M
authors.lastname: Kostadima
authors.forename: Paul
authors.initials: P
authors.lastname: Bertone
authors.forename: Martijn H
authors.initials: MH
authors.lastname: Breuning
authors.forename: Najet
authors.initials: N
authors.lastname: Debili
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Rémi
authors.initials: R
authors.lastname: Favier
authors.forename: Janine
authors.initials: J
authors.lastname: Fiedler
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Hobbs
authors.forename: Ni
authors.initials: N
authors.lastname: Huang
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.forename: Graham
authors.initials: G
authors.lastname: Kiddle
authors.forename: Ingrid
authors.initials: I
authors.lastname: Krapels
authors.forename: Paquita
authors.initials: P
authors.lastname: Nurden
authors.forename: Claudia A L
authors.initials: CA
authors.lastname: Ruivenkamp
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Sambrook
authors.forename: Kenneth
authors.initials: K
authors.lastname: Smith
authors.forename: Derek L
authors.initials: DL
authors.lastname: Stemple
authors.forename: Gabriele
authors.initials: G
authors.lastname: Strauss
authors.forename: Chantal
authors.initials: C
authors.lastname: Thys
authors.forename: Chris
authors.initials: C
authors.lastname: van Geet
authors.forename: Ruth
authors.initials: R
authors.lastname: Newbury-Ecob
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.forename: Cedric
authors.initials: C
authors.lastname: Ghevaert
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D000080984:Congenital Bone Marrow Failure Syndromes; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010976:Platelet Count; D020641:Polymorphism, Single Nucleotide; D016601:RNA-Binding Proteins / Q000235:genetics*; D011884:Radius / Q000002:abnormalities; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D013921:Thrombocytopenia / Q000151:congenital / Q000235:genetics*; D038062:Upper Extremity Deformities, Congenital / Q000235:genetics*; D055815:Young Adult; D015027:Zebrafish / Q000235:genetics
chemical_list: D020121:5' Untranslated Regions; C406243:RBM8A protein, human; D016601:RNA-Binding Proteins