De novo truncating variants in WHSC1 recapitulate the Wolf-Hirschhorn (4p16.3 microdeletion) syndrome phenotype
De novo truncating variants in WHSC1 recapitulate the Wolf-Hirschhorn (4p16.3 microdeletion) syndrome phenotype
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DOI：
10.1038/s41436-018-0014-8
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发表时间：
2019-01-01
影响因子：
8.8
通讯作者：
Alkuraya, Fowzan S.
中科院分区：
文献类型：
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作者：
Derar, Nada;Al-Hassnan, Zuhair N.;Alkuraya, Fowzan S.
目的：Wolf-Hirschhorn综合征(WHS)是一种由4p16.3基因的偏合引起的具有可识别的畸形特征的基因组疾病。以往的尝试未能将最小的关键基因定位到单个基因，留下了一种可能性，即该综合征的核心表型成分是由多个基因的联合单倍体不足引起的。方法：临床外显子组测序和“反向”表型分析。结果：我们在WHSC1中发现了两个新的截断变异的患者，该变异映射到WHS关键基因。这两个个体的表型与WHS是一致的，这表明WHSC1的单倍性不足足以概括这一经典微缺失综合征的核心表型(特征相、生长发育迟缓)。结论：我们的研究扩大了单基因水平解决的微缺失综合征的列表，并确立了WHSC1是人类的一种疾病基因。鉴于已报道的变异的严重性质，WHSC1的完整表型表达可能会因未来报道的较温和的变异而进一步扩大。
Purpose: Wolf-Hirschhorn syndrome (WHS) is a genomic disorder with a recognizable dysmorphology profile caused by hemizygosity at 4p16.3. Previous attempts have failed to map the minimal critical locus to a single gene, leaving open the possibility that the core phenotypic components of the syndrome are caused by the combined haploinsufficiency of multiple genes.Methods: Clinical exome sequencing and "reverse" phenotyping.Results: We identified two patients with de novo truncating variants in WHSC1, which maps to the WHS critical locus. The phenotype of these two individuals is consistent with WHS, which suggests that haploinsufficiency of WHSC1 is sufficient to recapitulate the core phenotype (characteristic facies, and growth and developmental delay) of this classic microdeletion syndrome.Conclusion: Our study expands the list of microdeletion syndromes that are solved at the single-gene level, and establishes WHSC1 as a disease gene in humans. Given the severe nature of the reported variants, the full phenotypic expression of WHSC1 may be further expanded by future reports of milder variants.