Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome

Cornelis A. Albers*, Dirk S. Paul, Harald Schulze, Kathleen Freson, Jonathan C. Stephens, Peter A. Smethurst, Jennifer D. Jolley, Ana Cvejic, Myrto Kostadima, Paul Bertone, Martijn H. Breuning, Najet Debili, Panos Deloukas, Remi Favier, Janine Fiedler, Catherine M. Hobbs, Ni Huang, Matthew E. Hurles, Graham Kiddle, Ingrid KrapelsPaquita Nurden, Claudia A. L. Ruivenkamp, Jennifer G. Sambrook, Kenneth Smith, Derek L. Stemple, Gabriele Strauss, Chantal Thys, Chris van Geet, Ruth Newbury-Ecob, Willem H. Ouwehand, Cedric Ghevaert

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


The exon-junction complex (EJC) performs essential RNA processing tasks(1-5). Here, we describe the first human disorder, thrombocytopenia with absent radii (TAR)(6), 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 x 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(7), 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.
Original languageEnglish
Pages (from-to)435-U248
JournalNature Genetics
Issue number4
Publication statusPublished - Apr 2012

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