Abstract：
OBJECTIVE: DEPDC5 emerges to play a vital role in focal epilepsy. However, genotype-phenotype correlation in DEPDC5-related focal epilepsies is challenging and controversial. In this study, we aim to investigate the genotypic and phenotypic features in DEPDC5-affected patients.
METHODS: Genetic testing combined with criteria published by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), was used to identify pathogenic/likely pathogenic variants in DEPDC5 among the cohort of 479 patients with focal epilepsy. Besides, the literature review was performed to explore the genotype-phenotype correlation and the penetrance in DEPDC5-related focal epilepsies.
RESULTS: Eight unrelated probands were revealed to carry different pathogenic/likely pathogenic variants in DEPDC5 and the total prevalence of DEPDC5-related focal epilepsy was 1.67% in the cohort. Sixty-five variants from 28 studies were included in our review. Combined with the cases reported, null variants accounted for a larger proportion than missense variants and were related to unfavorable prognosis (drug resistance or even sudden unexpected death in epilepsy; χ2 = 5.429, p = .020). And, the prognosis of probands with developmental delay/intellectual disability or focal cortical dysplasia was worse than that of probands with simple epilepsy (χ2 = -, p = .006). Besides, the overall penetrance of variants in DEPDC5 was 68.96% (231/335).
CONCLUSIONS: The study expands the variant spectrum of DEPDC5 and proves that the DEPDC5 variant plays a significant role in focal epilepsy. Due to the characteristics of phenotypic heterogeneity and incomplete penetrance, genetic testing is necessary despite no specific family history. And we propose to adopt the ACMG/AMP criteria refined by ClinGen Sequence Variant Interpretation Working Group, for consistency in usage and transparency in classification rationale. Moreover, we reveal an important message to clinicians that the prognosis of DEPDC5-affected patients is related to the variant type and complications.
METHODS: Genetic testing combined with criteria published by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), was used to identify pathogenic/likely pathogenic variants in DEPDC5 among the cohort of 479 patients with focal epilepsy. Besides, the literature review was performed to explore the genotype-phenotype correlation and the penetrance in DEPDC5-related focal epilepsies.
RESULTS: Eight unrelated probands were revealed to carry different pathogenic/likely pathogenic variants in DEPDC5 and the total prevalence of DEPDC5-related focal epilepsy was 1.67% in the cohort. Sixty-five variants from 28 studies were included in our review. Combined with the cases reported, null variants accounted for a larger proportion than missense variants and were related to unfavorable prognosis (drug resistance or even sudden unexpected death in epilepsy; χ2 = 5.429, p = .020). And, the prognosis of probands with developmental delay/intellectual disability or focal cortical dysplasia was worse than that of probands with simple epilepsy (χ2 = -, p = .006). Besides, the overall penetrance of variants in DEPDC5 was 68.96% (231/335).
CONCLUSIONS: The study expands the variant spectrum of DEPDC5 and proves that the DEPDC5 variant plays a significant role in focal epilepsy. Due to the characteristics of phenotypic heterogeneity and incomplete penetrance, genetic testing is necessary despite no specific family history. And we propose to adopt the ACMG/AMP criteria refined by ClinGen Sequence Variant Interpretation Working Group, for consistency in usage and transparency in classification rationale. Moreover, we reveal an important message to clinicians that the prognosis of DEPDC5-affected patients is related to the variant type and complications.
摘要：
目的：DEPDC5在局灶性癫痫中起重要作用。然而,DEPDC5相关局灶性癫痫的基因型-表型相关性具有挑战性且存在争议.在这项研究中,我们旨在调查DEPDC5患者的基因型和表型特征.
方法：基因检测与美国医学遗传学与基因组学学院和分子病理学协会（ACMG/AMP）发布的标准相结合，用于在479例局灶性癫痫患者队列中鉴定DEPDC5的致病/可能致病变异。此外,我们对DEPDC5相关局灶性癫痫的基因型-表型相关性和外显率进行了文献综述.
结果：发现8个无关的先证者在DEPDC5中携带不同的致病/可能致病变异，DEPDC5相关局灶性癫痫的总患病率为1.67%。来自28项研究的65个变体被纳入我们的综述。结合报告的病例，无效变异比错义变异占更大的比例，并且与预后不良（癫痫耐药甚至猝死；χ2=5.429，p=0.020）有关。And,发育迟缓/智力障碍或局灶性皮质发育不良的先证者的预后比单纯癫痫的先证者差（χ2=-，p=.006）。此外,DEPDC5中变体的总体外显率为68.96%(231/335).
结论：该研究扩展了DEPDC5的变异谱，并证明DEPDC5变异在局灶性癫痫中起着重要作用。由于表型异质性和不完全外显率的特点，基因检测是必要的，尽管没有具体的家族史。我们建议采用ClinGen序列变体解释工作组改进的ACMG/AMP标准，用于使用的一致性和分类基本原理的透明度。此外，我们向临床医生揭示了一个重要信息,即DEPDC5患者的预后与变异类型和并发症有关.
方法：基因检测与美国医学遗传学与基因组学学院和分子病理学协会（ACMG/AMP）发布的标准相结合，用于在479例局灶性癫痫患者队列中鉴定DEPDC5的致病/可能致病变异。此外,我们对DEPDC5相关局灶性癫痫的基因型-表型相关性和外显率进行了文献综述.
结果：发现8个无关的先证者在DEPDC5中携带不同的致病/可能致病变异，DEPDC5相关局灶性癫痫的总患病率为1.67%。来自28项研究的65个变体被纳入我们的综述。结合报告的病例，无效变异比错义变异占更大的比例，并且与预后不良（癫痫耐药甚至猝死；χ2=5.429，p=0.020）有关。And,发育迟缓/智力障碍或局灶性皮质发育不良的先证者的预后比单纯癫痫的先证者差（χ2=-，p=.006）。此外,DEPDC5中变体的总体外显率为68.96%(231/335).
结论：该研究扩展了DEPDC5的变异谱，并证明DEPDC5变异在局灶性癫痫中起着重要作用。由于表型异质性和不完全外显率的特点，基因检测是必要的，尽管没有具体的家族史。我们建议采用ClinGen序列变体解释工作组改进的ACMG/AMP标准，用于使用的一致性和分类基本原理的透明度。此外，我们向临床医生揭示了一个重要信息,即DEPDC5患者的预后与变异类型和并发症有关.
