Further evidence that de novo missense and truncating variants in ZBTB18 cause intellectual disability with variable features
Further evidence that de novo missense and truncating variants in ZBTB18 cause intellectual disability with variable features
复制标题
DOI：
10.1111/cge.12861
复制
发表时间：
2017-05-01
影响因子：
3.5
通讯作者：
Fatemi, A.
中科院分区：
文献类型：
--
作者：
Cohen, J. S.;Srivastava, S.;Fatemi, A.
下一代测序技术的进步大大加快了智力残疾（ID）患者中罕见遗传变异的鉴定。然而，由于患者数量较少，与单基因致病变异相关的完整表型谱仍在出现。在这些基因中，ZBTB 18（ZNF 238）在1 q43 q44微缺失的患者中缺失，这些患者通常表现为ID，小头畸形，胼胝体（CC）异常和癫痫发作。在这里，我们提供了额外的证据，单倍不足或功能障碍的ZBTB 18基因作为ID的原因在5个不相关的患者进行全外显子组测序显示单独的从头致病或可能致病的ZBTB 18变异（两个错义改变和三个截断改变）的可变综合征的功能。我们队列中的神经影像学发现（接受MRI的患者中有4/4可见CC发育不全）进一步支持ZBTB 18是CC异常的关键基因。中枢神经系统特异性敲除Zbtb 18的小鼠中也有类似的小头畸形、CC发育不全和小脑蚓部发育不全的表型。我们的五名患者，除了先前描述的新发ZBTB 18变异的病例外，还增加了关于与ZBTB 18单倍不足/功能障碍相关的表型谱的知识。
Identification of rare genetic variants in patients with intellectual disability (ID) has been greatly accelerated by advances in next generation sequencing technologies. However, due to small numbers of patients, the complete phenotypic spectrum associated with pathogenic variants in single genes is still emerging. Among these genes is ZBTB18 (ZNF238), which is deleted in patients with 1q43q44 microdeletions who typically present with ID, microcephaly, corpus callosum (CC) abnormalities, and seizures. Here we provide additional evidence for haploinsufficiency or dysfunction of the ZBTB18 gene as the cause of ID in five unrelated patients with variable syndromic features who underwent whole exome sequencing revealing separate de novo pathogenic or likely pathogenic variants in ZBTB18 (two missense alterations and three truncating alterations). The neuroimaging findings in our cohort (CC hypoplasia seen in 4/4 of our patients who underwent MRI) lend further support for ZBTB18 as a critical gene for CC abnormalities. A similar phenotype of microcephaly, CC agenesis, and cerebellar vermis hypoplasia has been reported in mice with central nervous system-specific knockout of Zbtb18. Our five patients, in addition to the previously described cases of de novo ZBTB18 variants, add to knowledge about the phenotypic spectrum associated with ZBTB18 haploinsufficiency/dysfunction.