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Clinical presentation of a complex neurodevelopmental disorder caused by mutations in ADNP
Biological Psychiatry ( IF 10.6 ) Pub Date : 2019-02-01 , DOI: 10.1016/j.biopsych.2018.02.1173
Anke Van Dijck 1 , Anneke T Vulto-van Silfhout 2 , Elisa Cappuyns 3 , Ilse M van der Werf 3 , Grazia M Mancini 4 , Andreas Tzschach 5 , Raphael Bernier 6 , Illana Gozes 7 , Evan E Eichler 8 , Corrado Romano 9 , Anna Lindstrand 10 , Ann Nordgren 10 , , Malin Kvarnung 10 , Tjitske Kleefstra 2 , Bert B A de Vries 2 , Sébastien Küry 11 , Jill A Rosenfeld 12 , Marije E Meuwissen 3 , Geert Vandeweyer 3 , R Frank Kooy 3
Affiliation  

BACKGROUND In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking. METHODS We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires. RESULTS We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected. CONCLUSIONS This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype.

中文翻译:

ADNP突变引起的复杂神经发育障碍的临床表现

背景 在针对自闭症和智力障碍的从头突变的全基因组筛查研究中,ADNP 基因的突变一直被报道为最常见的突变。已在患有自闭症谱系障碍的儿童中发现了 ADNP 突变,并伴有智力障碍、独特的面部特征和多器官系统的缺陷。然而,缺乏对 Helsmoortel-Van der Aa 综合征的全面临床描述。方法 我们通过系统文献检索、联系合作者以及与父母的直接互动,确定了 2014 年 1 月至 2016 年 10 月期间 ADNP 可能具有破坏性突变的全球 78 人队列。临床医生填写了一份关于遗传和临床发现的结构化问卷,以实现基因型和表型之间的相关性。收集了临床照片和专家报告。对家长进行了采访以补充书面问卷。结果 我们报告了大量具有 ADNP 突变的个体的详细临床特征,并展示了临床特征的独特组合,包括轻度至重度智力障碍、自闭症、严重的言语和运动迟缓以及常见的面部特征。大脑异常、行为问题、睡眠障碍、癫痫、肌张力减退、视力问题、先天性心脏缺陷、胃肠道问题、身材矮小和激素缺乏是常见的合并症。引人注目的是,具有复发性 p.Tyr719* 突变的个体受到的影响更为严重。结论 本概述定义了 ADNP 突变个体的完整临床谱,一种特定的自闭症亚型。我们表明,具有 ADNP 突变的个体具有许多与其他自闭症和/或智力残疾综合征不同的重叠临床特征。此外,我们的数据显示了基因型和表型之间相关性的初步证据。
更新日期:2019-02-01
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