Exome Sequencing Identifies a Recurrent De Novo ZSWIM6 Mutation Associated with Acromelic Frontonasal Dysostosis
Exome Sequencing Identifies a Recurrent De Novo ZSWIM6 Mutation Associated with Acromelic Frontonasal Dysostosis
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DOI：
10.1016/j.ajhg.2014.07.008
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发表时间：
2014-08-07
影响因子：
9.8
通讯作者：
Cunningham, Michael L.
中科院分区：
文献类型：
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作者：
Smith, Joshua D.;Hing, Anne V.;Cunningham, Michael L.
肢端性额鼻发育不全（AFND）是一种罕见的疾病，其特征是独特的颅面，脑和肢体畸形，包括额鼻发育不良，纵裂脂肪瘤，胼胝体发育不全，胫骨半肢畸形，足轴前多指畸形和智力残疾。对一个三人组和两个无关先证者的外显子组测序显示，在BMWIM 6的高度保守蛋白结构域中存在相同的杂合'变体（c.3487C>T [p.Arg1163Trp]）;该变体在1000个基因组数据、dbSNP或外显子组测序项目中尚未发现。对三个三联体的桑格验证证实了该变异是新发的，并且也存在于第四个孤立的先证者中。受精后24小时的早期斑马鱼胚胎原位杂交显示zswim 6在端脑表达，48小时开始在中脑、后脑和视网膜表达。后期小鼠胚胎的免疫组织化学显示，在所有三个胚层的衍生物中有组织特异性表达。对来自两个先证者的成骨细胞和成纤维细胞系的gRT-PCR表达分析提示Hedgehog途径激活，表明与AFND相关的BMWIM 6突变可能通过Hedgehog信号传导的破坏导致颅面、脑和肢体畸形。
Acromelic frontonasal dysostosis (AFND) is a rare disorder characterized by distinct craniofacial, brain, and limb malformations, including frontonasal dysplasia, interhemispheric lipoma, agenesis of the corpus callosum, tibial hemimelia, preaxial polydactyly of the feet, and intellectual disability. Exome sequencing of one trio and two unrelated probands revealed the same heterozygous 'variant (c.3487C>T [p. Arg1163Trp]) in a highly conserved protein domain of ZSWIM6; this variant has not been seen in the 1000 Genomes data, dbSNP, or the Exome Sequencing Project. Sanger validation of the three trios confirmed that the variant was de novo and was also present in a fourth isolated proband. In situ hybridization of early zebrafish embryos at 24 hr postfertilization (hpf) demonstrated telencephalic expression of zswim6 and onset of midbrain, hindbrain, and retinal expression at 48 hpf. Immunohistochemistry of later-stage mouse embryos demonstrated tissue-specific expression in the derivatives of all three germ layers. gRT-PCR expression analysis of osteoblast and fibroblast cell lines available from two probands was suggestive of Hedgehog pathway activation, indicating that the ZSWIM6 mutation associated with AFND may lead to the craniofacial, brain and limb malformations through the disruption of Hedgehog signaling.