De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism
De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism
复制标题
DOI：
10.1016/j.ajhg.2019.02.023
复制
发表时间：
2019-04-04
影响因子：
9.8
通讯作者：
Jongmans, Marjolijn C. J.
中科院分区：
文献类型：
--
作者：
Diets, Illja J.;van der Donk, Roos;Jongmans, Marjolijn C. J.
通过外显子组测序和基因匹配方法，我们在14名不相关个体和3名不同程度的智力残疾（ID）或发育迟缓（DD）和身材矮小的受影响父母中发现了KDM3B的新生和遗传致病性变异。这些个体具有额外的表型特征，包括婴儿期喂养困难、关节过度活动和特征面部特征，如宽口、尖下巴、长耳朵和低鼻梁。值得注意的是，两个人在童年时期患上了癌症，急性髓性白血病和霍奇金淋巴瘤。KDM3B编码组蛋白去甲基化酶，并参与H3K9去甲基化，这是转录调节所需的染色质修饰的关键部分。我们发现了错义和截断变异，表明KDM3B单倍不足是该综合征的潜在机制。通过使用混合面部识别模型，我们发现具有KDM3B致病变异的个体具有面部完形，并且与具有ID的对照个体相比，他们表现出显着的面部相似性。总之，KDM3B的致病变异导致以ID、身材矮小和面部畸形为特征的综合征。
By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature. The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella. Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood. KDM3B encodes for a histone demethylase and is involved in H3K9 demethylation, a crucial part of chromatin modification required for transcriptional regulation. We identified missense and truncating variants, suggesting that KDM3B haploinsufficiency is the underlying mechanism for this syndrome. By using a hybrid facial-recognition model, we show that individuals with a pathogenic variant in KDM3B have a facial gestalt, and that they show significant facial similarity compared to control individuals with ID. In conclusion, pathogenic variants in KDM3B cause a syndrome characterized by ID, short stature, and facial dysmorphism.