PURPOSE Germline WWOX pathogenic variants have been associated with disorder of sex differentiation (DSD), spinocerebellar ataxia (SCA), and WWOX-related epileptic encephalopathy (WOREE syndrome). We review clinical and molecular data on WWOX-related disorders, further describing WOREE syndrome and phenotype/genotype correlations. METHODS We report clinical and molecular findings in 20 additional patients from 18 unrelated families with WOREE syndrome and biallelic pathogenic variants in the WWOX gene. Different molecular screening approaches were used (quantitative polymerase chain reaction/multiplex ligation-dependent probe amplification [qPCR/MLPA], array comparative genomic hybridization [array-CGH], Sanger sequencing, epilepsy gene panel, exome sequencing), genome sequencing. RESULTS Two copy-number variations (CNVs) or two single-nucleotide variations (SNVs) were found respectively in four and nine families, with compound heterozygosity for one SNV and one CNV in five families. Eight novel missense pathogenic variants have been described. By aggregating our patients with all cases reported in the literature, 37 patients from 27 families with WOREE syndrome are known. This review suggests WOREE syndrome is a very severe epileptic encephalopathy characterized by absence of language development and acquisition of walking, early-onset drug-resistant seizures, ophthalmological involvement, and a high likelihood of premature death. The most severe clinical presentation seems to be associated with null genotypes. CONCLUSION Germline pathogenic variants in WWOX are clearly associated with a severe early-onset epileptic encephalopathy. We report here the largest cohort of individuals with WOREE syndrome.

中文翻译：

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WWOX 相关疾病的表型谱：另外 20 例 WOEE 综合征病例和文献回顾。

目的 生殖系 WWOX 致病变异与性别分化障碍 (DSD)、脊髓小脑共济失调 (SCA) 和 WWOX 相关的癫痫性脑病 (WOEE 综合征) 相关。我们回顾了 WWOX 相关疾病的临床和分子数据，进一步描述了 WOEE 综合征和表型/基因型相关性。方法 我们报告了另外 20 名来自 18 个无关家族的 WOEE 综合征和 WWOX 基因双等位基因致病变异的患者的临床和分子学发现。使用了不同的分子筛选方法（定量聚合酶链式反应/多重连接依赖性探针扩增 [qPCR/MLPA]、阵列比较基因组杂交 [array-CGH]、Sanger 测序、癫痫基因组、外显子组测序）、基因组测序。结果 4个和9个家系分别发现2个拷贝数变异（CNVs）或2个单核苷酸变异（SNVs），5个家系有1个SNV和1个CNV的复合杂合性。已经描述了八种新的错义致病变异。通过将我们的患者与文献中报道的所有病例汇总，已知来自 27 个 WOEE 综合征家庭的 37 名患者。这篇综述表明 WOEE 综合征是一种非常严重的癫痫性脑病，其特征是缺乏语言发育和行走能力、早发性耐药性癫痫发作、眼科受累和过早死亡的高可能性。最严重的临床表现似乎与无效基因型有关。结论 WWOX 中的胚系致病变异与严重的早发性癫痫性脑病明显相关。我们在这里报告了最大的 WOEE 综合征患者队列。