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.

中文翻译：

---

WDR83OS纯合子变异导致伴有高胆汁血症的神经发育障碍


WD 重复结构域 83 相反链 （WDR83OS） 编码 106-aa（氨基酸）蛋白 Asterix，该蛋白与 CCDC47 异二聚化形成 PAT（与 ER 转位菌相关的蛋白）复合物。该复合物可作为含有跨膜结构域的大蛋白的伴侣，以确保正确折叠。直到最近，人们对 WDR83OS 或 CCDC47 在人类疾病特征中的作用知之甚少。然而，CCDC47 的双等位基因变异在 4 个不相关的毛肝神经发育综合征家族中被发现，其特征是伴有肝功能障碍的神经发育障碍 （NDD）。另一个家庭中的 3 个受影响的兄弟姐妹共享一个纯合截短 WDR83OS 变体和一个 NDD 表型、畸形特征和肝功能障碍。使用基于家族的外显子组测序 （ES） 数据和通过 GeneMatcher 进行的病例匹配，我们描述了 8 个不相关家族 （9 个无关家族，总共 14 个个体） 中另外 11 个个体的临床表型，在 WDR83OS 中具有双等位基因推定截短变异。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 5/6 的受测个体胆汁酸显着升高，但所有 14 个个体的胆红素正常，肝酶正常或轻度升高。在有纵向数据的 6 个个体中，有 3 个个体观察到相对头围逐渐减少。缺乏 Wdr83os 功能的斑马鱼模型进一步支持其在神经系统、颅面发育和脂质吸收中的作用。 综上所述，我们的数据支持 WDR83OS 双等位基因功能丧失与高胆汁血症的神经系统疾病特征之间的疾病-基因关联。