Homozygous variants in WDR83OS lead to a neurodevelopmental disorder with hypercholanemia.

IF 8.1 1区 生物学 Q1 GENETICS & HEREDITY American journal of human genetics Pub Date : 2024-11-07 Epub Date: 2024-10-28 DOI:10.1016/j.ajhg.2024.10.002
Scott Barish, Sheng-Jia Lin, Reza Maroofian, Alper Gezdirici, Hamoud Alhebby, Aurélien Trimouille, Marta Biderman Waberski, Tadahiro Mitani, Ilka Huber, Kristian Tveten, Øystein L Holla, Øyvind L Busk, Henry Houlden, Ehsan Ghayoor Karimiani, Mehran Beiraghi Toosi, Reza Shervin Badv, Paria Najarzadeh Torbati, Fatemeh Eghbal, Javad Akhondian, Ayat Al Safar, Abdulrahman Alswaid, Giovanni Zifarelli, Peter Bauer, Dana Marafi, Jawid M Fatih, Kevin Huang, Cassidy Petree, Daniel G Calame, Charlotte von der Lippe, Fowzan S Alkuraya, Sami Wali, James R Lupski, Gaurav K Varshney, Jennifer E Posey, Davut Pehlivan
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Abstract

WD repeat domain 83 opposite strand (WDR83OS) encodes the 106-aa (amino acid) protein Asterix, which heterodimerizes with CCDC47 to form the PAT (protein associated with ER translocon) complex. This complex functions as a chaperone for large proteins containing transmembrane domains to ensure proper folding. Until recently, little was known about the role of WDR83OS or CCDC47 in human disease traits. However, biallelic variants in CCDC47 were identified in four unrelated families with trichohepatoneurodevelopmental syndrome, characterized by a neurodevelopmental disorder (NDD) with liver dysfunction. Three affected siblings in an additional family share a homozygous truncating WDR83OS variant and a phenotype of NDD, dysmorphic features, and liver dysfunction. Using family-based rare variant analyses of exome sequencing (ES) data and case matching through GeneMatcher, we describe the clinical phenotypes of 11 additional individuals in eight unrelated families (nine unrelated families, 14 individuals in total) with biallelic putative truncating variants in WDR83OS. Consistent clinical features include NDD (14/14), facial dysmorphism (13/14), intractable itching (9/14), and elevated bile acids (5/6). Whereas bile acids were significantly elevated in 5/6 of individuals tested, bilirubin was normal and liver enzymes were normal to mildly elevated in all 14 individuals. In three of six individuals for whom longitudinal data were available, we observed a progressive reduction in relative head circumference. A zebrafish model lacking Wdr83os function further supports its role in the nervous system, craniofacial development, and lipid absorption. Taken together, our data support a disease-gene association between biallelic loss-of-function of WDR83OS and a neurological disease trait with hypercholanemia.

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WDR83OS的同源变异会导致一种伴有高胆汁血症的神经发育障碍。
WD 重复结构域 83 反向链(WDR83OS)编码 106-aa (氨基酸)蛋白质 Asterix,它与 CCDC47 异源二聚体形成 PAT(与 ER 易位子相关的蛋白质)复合体。该复合体的功能是作为含有跨膜结构域的大型蛋白质的伴侣,以确保适当的折叠。直到最近,人们对 WDR83OS 或 CCDC47 在人类疾病特征中的作用还知之甚少。然而,在四个无血缘关系的三肝神经发育综合征(Trichohepatoneurodevelopmental Syndrome)家族中发现了CCDC47的双倍变体。在另一个家族中,三个受影响的兄弟姐妹都有一个同源的截断WDR83OS变体,其表型为NDD、畸形特征和肝功能异常。利用基于家族的外显子组测序(ES)数据罕见变异分析和通过 GeneMatcher 进行的病例配对,我们描述了 8 个无血缘关系家族(9 个无血缘关系家族,共 14 人)中另外 11 个具有 WDR83OS 双倍推定截断变异的个体的临床表型。一致的临床特征包括 NDD(14/14)、面部畸形(13/14)、顽固性瘙痒(9/14)和胆汁酸升高(5/6)。虽然胆汁酸在 5/6 例受检者中明显升高,但胆红素正常,所有 14 例受检者的肝酶正常至轻度升高。在有纵向数据的 6 个个体中,我们观察到其中 3 个个体的相对头围逐渐缩小。缺乏 Wdr83os 功能的斑马鱼模型进一步证实了它在神经系统、颅面部发育和脂质吸收中的作用。总之,我们的数据支持 WDR83OS 双倍子功能缺失与神经系统疾病特征和高胆汁血症之间的疾病基因关联。
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来源期刊
CiteScore
14.70
自引率
4.10%
发文量
185
审稿时长
1 months
期刊介绍: The American Journal of Human Genetics (AJHG) is a monthly journal published by Cell Press, chosen by The American Society of Human Genetics (ASHG) as its premier publication starting from January 2008. AJHG represents Cell Press's first society-owned journal, and both ASHG and Cell Press anticipate significant synergies between AJHG content and that of other Cell Press titles.
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