Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes nager syndrome

Francois P. Bernier, Oana Caluseriu, Sarah Ng, Jeremy Schwartzentruber, Kati J. Buckingham, A. Micheil Innes, Ethylin Wang Jabs, Jeffrey W. Innis, Jane L. Schuette, Jerome L. Gorski, Peter H. Byers, Gregor Andelfinger, Victoria Siu, Julie Lauzon, Bridget A. Fernandez, Margaret McMillin, Richard H. Scott, Hilary Racher, Jacek Majewski, Deborah A. NickersonJay Shendure, Michael J. Bamshad, Jillian S. Parboosingh

Research output: Contribution to journalArticlepeer-review

114 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)925-933
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number5
StatePublished - May 4 2012
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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