Haploinsufficiency of SF3B2 causes craniofacial microsomia.

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. Despite being a common congenital facial anomaly, the genetic etiology of craniofacial microsomia (CFM) is not well understood. Here, the authors use exome and genome sequencing of 146 individuals with CFM to identify haploinsufficient variants in SF3B2 as a prevalent underlying cause.

颅面短小畸形（CFM）是第二常见的先天性面部异常，然而其遗传病因仍不清楚。我们对146个散发（n = 138）或家族性（n = 8）CFM家系进行了全外显子组或基因组测序，在患者中发现SF3B2（P = 3.8×10⁻¹⁰）中存在功能缺失变异的高度显著负担，SF3B2是U2小核核糖核蛋白复合物的一个组分。我们描述了来自7个家系的20名个体，其携带SF3B2的新生或遗传的单倍体不足变异。患者表现出下颌发育不全、小耳畸形、面部和耳前赘生物、眼球表面皮样囊肿、外侧唇腭裂以及骨骼和心脏异常。在非洲爪蟾中靶向敲低SF3B2会导致颅神经嵴前体细胞形成中断以及随后的颅面软骨缺陷，这支持了剪接体突变与先天性颅面疾病中神经嵴发育受损之间的联系。研究结果确定SF3B2的单倍体不足变异是CFM最常见的遗传原因，可解释约3%的散发病例和约25%的家族性病例。 尽管颅面短小畸形是一种常见的先天性面部异常，但其遗传病因尚未得到充分了解。在此，作者对146名CFM患者进行外显子组和基因组测序，以确定SF3B2的单倍体不足变异是一种普遍的潜在病因。