Haploinsufficiency of SF3B2 causes craniofacial microsomia.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Timberlake Andrew T, Griffin Casey, Heike Carrie L, Hing Anne V, Cunningham Michael L, Chitayat David, Davis Mark R, Doust Soghra J, Drake Amelia F, Duenas-Roque Milagros M, Goldblatt Jack, Gustafson Jonas A, Hurtado-Villa Paula, Johns Alexis, Karp Natalya, Laing Nigel G, Magee Leanne, University of Washington Center for Mendelian Genomics, Mullegama Sureni V, Pachajoa Harry, Porras-Hurtado Gloria L, Schnur Rhonda E, Slee Jennie, Singer Steven L, Staffenberg David A, Timms Andrew E, Wise Cheryl A, Zarante Ignacio, Saint-Jeannet Jean-Pierre, Luquetti Daniela V
Аннотация
Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, yet its genetic etiology remains unknown. We perform whole-exome or genome sequencing of 146 kindreds with sporadic (n = 138) or familial (n = 8) CFM, identifying a highly significant burden of loss of function variants in SF3B2 (P = 3.8 × 10-10), a component of the U2 small nuclear ribonucleoprotein complex, in probands. We describe twenty individuals from seven kindreds harboring de novo or transmitted haploinsufficient variants in SF3B2. Probands display mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities. Targeted morpholino knockdown of SF3B2 in Xenopus results in disruption of cranial neural crest precursor formation and subsequent craniofacial cartilage defects, supporting a link between spliceosome mutations and impaired neural crest development in congenital craniofacial disease. The results establish haploinsufficient variants in SF3B2 as the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases.