TY - JOUR
T1 - Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes nager syndrome
AU - Bernier, Francois P.
AU - Caluseriu, Oana
AU - Ng, Sarah
AU - Schwartzentruber, Jeremy
AU - Buckingham, Kati J.
AU - Innes, A. Micheil
AU - Jabs, Ethylin Wang
AU - Innis, Jeffrey W.
AU - Schuette, Jane L.
AU - Gorski, Jerome L.
AU - Byers, Peter H.
AU - Andelfinger, Gregor
AU - Siu, Victoria
AU - Lauzon, Julie
AU - Fernandez, Bridget A.
AU - McMillin, Margaret
AU - Scott, Richard H.
AU - Racher, Hilary
AU - Majewski, Jacek
AU - Nickerson, Deborah A.
AU - Shendure, Jay
AU - Bamshad, Michael J.
AU - Parboosingh, Jillian S.
PY - 2012/5/4
Y1 - 2012/5/4
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2012.04.004
DO - 10.1016/j.ajhg.2012.04.004
M3 - Article
C2 - 22541558
AN - SCOPUS:84860729127
VL - 90
SP - 925
EP - 933
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 5
ER -