Biallelic mutation of FBXL7 suggests a novel form of Hennekam syndrome
Biallelic mutation of FBXL7 suggests a novel form of Hennekam syndrome
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DOI：
10.1002/ajmg.a.61392
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发表时间：
2019-10-21
影响因子：
2
通讯作者：
Rodan, Lance H.
中科院分区：
文献类型：
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作者：
Boone, Philip M.;Paterson, Scott;Rodan, Lance H.
Hennekam淋巴管扩张-肠水肿综合征是一种常染色体隐性遗传疾病，其特征是先天性肠水肿、肠淋巴管扩张、面部畸形和各种智力残疾。已知的疾病基因包括CCBE 1、FAT 4和ADAMTS 3。在临床诊断为Hennekam综合征但三个已知疾病基因没有突变或拷贝数变化的患者中，我们确定了影响FBXL 7的纯合单外显子缺失。具体而言，外显子3，其编码的F-box结构域和几个富含亮氨酸的重复FBXL 7，被删除。我们对代表> 100，000个对照个体的数据库的分析未能鉴定FBXL 7中的双等位基因功能丧失变体。在果蝇中发表的研究表明Fbxl 7与Fat相互作用，其中人FAT 4是直系同源物，并且任一基因的突变产生相似的形态学结果。这些数据表明FBXL 7可能是Hennekam综合征的第四个基因，通过与FAT 4共享的途径起作用。
Hennekam lymphangiectasia-lymphedema syndrome is an autosomal recessive disorder characterized by congenital lymphedema, intestinal lymphangiectasia, facial dysmorphism, and variable intellectual disability. Known disease genes include CCBE1, FAT4, and ADAMTS3. In a patient with clinically diagnosed Hennekam syndrome but without mutations or copy-number changes in the three known disease genes, we identified a homozygous single-exon deletion affecting FBXL7. Specifically, exon 3, which encodes the F-box domain and several leucine-rich repeats of FBXL7, is eliminated. Our analyses of databases representing >100,000 control individuals failed to identify biallelic loss-of-function variants in FBXL7. Published studies in Drosophila indicate Fbxl7 interacts with Fat, of which human FAT4 is an ortholog, and mutation of either gene yields similar morphological consequences. These data suggest that FBXL7 may be the fourth gene for Hennekam syndrome, acting via a shared pathway with FAT4.