Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Clin Genet. 2017 Oct;92(4):380-387. doi: 10.1111/cge.12979. Epub 2017 Mar 7.
Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare, genetically heterogeneous, autosomal recessive disorder. Patients suffer from recurrent infections caused by reduced levels or absence of serum immunoglobulins. Genetically, 4 subtypes of ICF syndrome have been identified to date: ICF1 (DNMT3B mutations), ICF2 (ZBTB24 mutations), ICF3 (CDCA7 mutations), and ICF4 (HELLS mutations).
To study the mutation spectrum in ICF syndrome.
Genetic studies were performed in peripheral blood lymphocyte DNA from suspected ICF patients and family members.
We describe 7 ICF1 patients and 6 novel missense mutations in DNMT3B, affecting highly conserved residues in the catalytic domain. We also describe 5 new ICF2 patients, one of them carrying a homozygous deletion of the complete ZBTB24 locus. In a meta-analysis of all published ICF cases, we observed a gender bias in ICF2 with 79% male patients.
The biallelic deletion of ZBTB24 provides strong support for the hypothesis that most ICF2 patients suffer from a ZBTB24 loss of function mechanism and confirms that complete absence of ZBTB24 is compatible with human life. This is in contrast to the observed early embryonic lethality in mice lacking functional Zbtb24. The observed gender bias seems to be restricted to ICF2 as it is not observed in the ICF1 cohort.
Our study expands the mutation spectrum in ICF syndrome and supports that DNMT3B and ZBTB24 are the most common disease genes.
免疫缺陷、着丝粒不稳定和面部异常（ICF）综合征是一种罕见的、遗传异质性的常染色体隐性疾病。患者由于血清免疫球蛋白水平降低或缺失而反复感染。从遗传学角度来看，迄今为止已经确定了 4 种 ICF 综合征亚型：ICF1（DNMT3B 突变）、ICF2（ZBTB24 突变）、ICF3（CDCA7 突变）和 ICF4（HELLS 突变）。
研究 ICF 综合征的突变谱。
对疑似 ICF 患者和家庭成员的外周血淋巴细胞 DNA 进行遗传研究。
我们描述了 7 例 ICF1 患者和 6 种新的 DNMT3B 错义突变，影响催化结构域中高度保守的残基。我们还描述了 5 例新的 ICF2 患者，其中 1 例携带 ZBTB24 完整基因座的纯合缺失。在对所有已发表的 ICF 病例进行的荟萃分析中，我们观察到 ICF2 存在性别偏倚，其中 79%的患者为男性。
ZBTB24 的双等位基因缺失为大多数 ICF2 患者存在 ZBTB24 功能丧失机制提供了有力支持，并证实完全缺乏 ZBTB24 与人类生命相容。这与缺乏功能性 Zbtb24 的小鼠中观察到的早期胚胎致死性形成鲜明对比。观察到的性别偏倚似乎仅限于 ICF2，因为在 ICF1 队列中没有观察到这种情况。
本研究扩展了 ICF 综合征的突变谱，并支持 DNMT3B 和 ZBTB24 是最常见的疾病基因。
