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首页> 外文期刊>The American Journal of Human Genetics >De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism
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De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism

机译：De Novo和遗传性致病变异在KDM3B中引起智力残疾，身材矮小和面部钝象

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摘要

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.
机译：通过使用exome测序和基因匹配方法，我们在14个无关个体和三个受影响的父母中鉴定了KDM3B中的遗传性致病变异，具有不同程度的智力残疾（ID）或发育延迟（DD）和矮小的身材。该个人分享额外的表型特征，包括喂养婴儿期，关节高兴和特征面部特征，例如宽口，尖锐的下巴，长耳和低孔氏菌属的困难。值得注意的是，两个人在童年时期发育癌症，急性髓性白血病和霍奇金淋巴瘤。 KDM3B对组蛋白脱甲基化酶进行编码并参与H3K9去甲基化，转录调控所需的染色质修饰的关键部分。我们确定了畸形和截断的变体，表明KDM3B臭氧水能是该综合征的潜在机制。通过使用混合面部识别模型，我们表明KDM3B中具有致病变体的个体具有面部甲型，并且它们与具有ID的控制的个体相比显示出显着的面部相似性。总之，KDM3B中的致病变体导致综合征，其特征在于ID，矮小和面部钝象。

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    Diets Illja J.; van der Donk Roos; Baltrunaite Kristina; Waanders Esme; Reijnders Margot R. F.; Dingemans Alexander J. M.; Pfundt Rolph; Vulto-van Silfhout Anneke T.; Wiel Laurens; Gilissen Christian; Thevenon Julien; Perrin Laurence; Afenjar Alexandra; Nava Caroline; Keren Boris; Bartz Sarah; Peri Bethany; Beunders Gea; Verbeek Nienke; van Gassen Koen; Thiffault Isabelle; Cadieux-Dion Maxime; Huerta-Saenz Lina; Wagner Matias; Konstantopoulou Vassiliki; Vodopiutz Julia; Griese Matthias; Boel Annekatrien; Callewaert Bert; Brunner Han G.; Kleefstra Tjitske; Hoogerbrugge Nicoline; de Vries Bert B. A.; Hwa Vivian; Dauber Andrew; Hehir-Kwa Jayne Y.; Kuiper Roland P.; Jongmans Marjolijn C. J.;

  • 作者单位

    Radboud Univ Nijmegen Med Ctr Dept Human Genet NL-6525 GA Nijmegen Netherlands;

    Radboud Univ Nijmegen Med Ctr Dept Human Genet NL-6525 GA Nijmegen Netherlands;

    Univ Cincinnati Cincinnati Childrens Hosp Med Ctr Dept Pediat Coll Med Div Endocrinol Cincinnati;

    Princess Maxima Ctr Pediat Oncol NL-3584 CS Utrecht Netherlands;

    Radboud Univ Nijmegen Med Ctr Dept Human Genet NL-6525 GA Nijmegen Netherlands;

    Radboud Univ Nijmegen Med Ctr Dept Human Genet NL-6525 GA Nijmegen Netherlands;

    Radboud Univ Nijmegen Med Ctr Dept Human Genet NL-6525 GA Nijmegen Netherlands;

    Radboud Univ Nijmegen Med Ctr Dept Human Genet NL-6525 GA Nijmegen Netherlands;

    Radboud Univ Nijmegen Med Ctr Dept Human Genet NL-6525 GA Nijmegen Netherlands;

    Radboud Univ Nijmegen Med Ctr Dept Human Genet NL-6525 GA Nijmegen Netherlands;

    CHU Dijon Hop Enfants Ctr Genet F-21079 Dijon France;

    CHU Dijon Hop Enfants Ctr Genet F-21079 Dijon France;

    Hop Armand Trousseau AP HP Ctr Reference Deficiences Intellectuelles Causes Dept Genet &

    Embryol;

    Hop La Pitie Salpetriere AP HP Dept Genet F-75013 Paris France;

    Hop La Pitie Salpetriere AP HP Dept Genet F-75013 Paris France;

    Childrens Hosp Colorado Div Endocrinol Aurora CO 80045 USA;

    Childrens Hosp Colorado Div Endocrinol Aurora CO 80045 USA;

    Vrije Univ Amsterdam Med Ctr Dept Clin Genet NL-1081 HV Amsterdam Netherlands;

    Univ Med Ctr Utrecht Dept Genet NL-3508 AB Utrecht Netherlands;

    Univ Med Ctr Utrecht Dept Genet NL-3508 AB Utrecht Netherlands;

    Childrens Mercy Hosp Ctr Pediat Genom Med Kansas City MO 66211 USA;

    Childrens Mercy Hosp Ctr Pediat Genom Med Kansas City MO 66211 USA;

    Childrens Mercy Hosp Kansas City MO 66211 USA;

    Tech Univ Munich Inst Human Genet D-80333 Munich Germany;

    Med Univ Vienna Dept Pediat &

    Adolescent Med A-1090 Vienna Austria;

    Med Univ Vienna Dept Pediat &

    Adolescent Med A-1090 Vienna Austria;

    Univ Hosp Munich German Ctr Lung Res Div Pediat Pneumol Dr von Hauner Childrens Hosp D-80333;

    Ghent Univ Hosp Ctr Med Genet B-9000 Ghent Belgium;

    Ghent Univ Hosp Ctr Med Genet B-9000 Ghent Belgium;

    Radboud Univ Nijmegen Med Ctr Dept Human Genet NL-6525 GA Nijmegen Netherlands;

    Radboud Univ Nijmegen Med Ctr Dept Human Genet NL-6525 GA Nijmegen Netherlands;

    Radboud Univ Nijmegen Med Ctr Dept Human Genet NL-6525 GA Nijmegen Netherlands;

    Radboud Univ Nijmegen Med Ctr Dept Human Genet NL-6525 GA Nijmegen Netherlands;

    Univ Cincinnati Cincinnati Childrens Hosp Med Ctr Dept Pediat Coll Med Div Endocrinol Cincinnati;

    Univ Cincinnati Cincinnati Childrens Hosp Med Ctr Dept Pediat Coll Med Div Endocrinol Cincinnati;

    Princess Maxima Ctr Pediat Oncol NL-3584 CS Utrecht Netherlands;

    Radboud Univ Nijmegen Med Ctr Dept Human Genet NL-6525 GA Nijmegen Netherlands;

    Radboud Univ Nijmegen Med Ctr Dept Human Genet NL-6525 GA Nijmegen Netherlands;

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  • 正文语种 eng
  • 中图分类 医学遗传学;
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