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The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype-phenotype correlations, and molecular basis.
Genetics in Medicine ( IF 6.6 ) Pub Date : 2019-08-07 , DOI: 10.1038/s41436-019-0612-0
Karin Weiss 1 , Hayley P Lazar 2 , Alina Kurolap 1, 3 , Ariel F Martinez 4 , Tamar Paperna 1 , Lior Cohen 5 , Marie F Smeland 6 , Sandra Whalen 7 , Solveig Heide 8 , Boris Keren 8 , Pauline Terhal 9 , Melita Irving 10 , Motoki Takaku 2 , John D Roberts 2 , Robert M Petrovich 2 , Samantha A Schrier Vergano 11, 12 , Amy Kenney 11 , Hanne Hove 13 , Elizabeth DeChene 14 , Shane C Quinonez 15 , Estelle Colin 16 , Alban Ziegler 16 , Melissa Rumple 17 , Mahim Jain 4, 18 , Danielle Monteil 19 , Elizabeth R Roeder 20 , Kimberly Nugent 20 , Arie van Haeringen 21 , Michael Gambello 22 , Avni Santani 14 , Līvija Medne 23 , Bryan Krock 14 , Cara M Skraban 23 , Elaine H Zackai 23 , Holly A Dubbs 24 , Thomas Smol 25, 26 , Jamal Ghoumid 25, 26 , Michael J Parker 27 , Michael Wright 28 , Peter Turnpenny 29 , Jill Clayton-Smith 30, 31 , Kay Metcalfe 30, 31 , Hitoshi Kurumizaka 32 , Bruce D Gelb 33 , Hagit Baris Feldman 1, 3 , Philippe M Campeau 34 , Maximilian Muenke 4 , Paul A Wade 2 , Katherine Lachlan 35
Affiliation  

PURPOSE Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical spectrum of the disorder, genotype-phenotype correlations, and the effect of different missense variants on CHD4 function. METHODS We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains. RESULTS The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype-phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains. CONCLUSION The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.

中文翻译:


CHD4 相关综合征:临床谱、基因型-表型相关性和分子基础的全面调查。



目的 Sifrim-Hitz-Weiss 综合征 (SIHIWES) 是一种最近描述的由 CHD4 中的新发变异引起的多系统神经发育障碍。在这项研究中,我们调查了该疾病的临床谱、基因型-表型相关性以及不同错义变异对 CHD4 功能的影响。方法 我们收集了 32 名个体的临床和分子数据,其中大部分是 CHD4 的新发变异,通过下一代测序鉴定。我们对来自五个不同 CHD4 结构域的变体进行了三磷酸腺苷 (ATP) 水解和核小体重塑测定。结果 大多数参与者有整体发育迟缓、轻度至中度智力障碍、脑异常、先天性心脏缺陷和畸形特征。大头畸形是一种常见但并非普遍的发现。其他常见异常包括男性性腺功能减退、骨骼和肢体异常、听力障碍和眼科异常。大多数变体是非截短的,并影响蛋白质的 SNF2 样区域。我们没有根据变异的类型或位置来识别基因型 - 表型相关性。在来自不同域的变体中观察到 ATP 水解和染色质重塑活性的改变。结论 CHD4 相关综合征是一种多系统神经发育障碍。不同蛋白质结构域中的错义替换以变体特异性方式改变 CHD4 功能,但在人类中导致相似的表型。
更新日期:2019-08-06
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