Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, 610041, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, China.
Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, 610041, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, China.
Epilepsy Res. 2021 Feb;170:106552. doi: 10.1016/j.eplepsyres.2021.106552. Epub 2021 Jan 7.
The aim of this retrospective study is to investigate the genetic etiology and propose a diagnostic strategy for pediatric patients with epilepsy and comorbid intellectual disability (ID).
From September 2014 to May 2020, a total of 102 pediatric patients diagnosed with epilepsy with co-morbid ID with unknown causes were included in this study. All patients underwent tests of single nucleotide polymorphism (SNP) array for chromosomal abnormalities. Whole exome sequencing (WES) was consecutively performed in patients without diagnostic copy number variants (CNVs) (n = 85) for single nucleotide variants (SNVs). Subgroup analyses based on the age of seizure onset and ID severity were done.
The overall diagnostic yield of genetic aberrations was 33.3 % (34/102), which comprised 50.0 % with diagnostic CNVs and 50.0 % with diagnostic SNVs. The yield nominally increased with ID severity and decreased with age of seizure onset, though this result was not statistically significant. The diagnostic yield of SNVs in patients with seizure onset in the first year of life (25.0 % (11/44)) was significantly higher than those with childhood-onset epilepsy (10.3 % (6/58)) (p = 0.049), however, the diagnostic yield of CNVs in patients with childhood-onset epilepsy (17.2 % (10/58) was higher than the diagnostic yield of SNVs (10.3 % (6/58)). The most frequently syndromic epilepsy detected by SNP array was Angelman syndrome (n=4), including one confirmed with paternal uniparental disomy. Meanwhile, the most frequent SNVs were mutations of MECP2 (n=2) and IQSEC2 (n = 2) in sporadic cases.
Both CMA and WES are advantageous as unbiased approaches for a genetically heterogeneous condition. We proposed an effective diagnostic strategy for pediatric patients with epilepsy. For patients with seizure onset in the first year of life, WES is recommended as the first-tier test. However, for patients with childhood-onset epilepsy, SNP array should be considered for the first-tier test.
本回顾性研究旨在探讨儿科癫痫伴智力障碍（ID）患者的遗传病因，并提出诊断策略。
本研究纳入了 2014 年 9 月至 2020 年 5 月期间共 102 例病因不明的伴发 ID 的儿科癫痫患者。所有患者均接受了染色体异常的单核苷酸多态性（SNP）微阵列检测。对无诊断性拷贝数变异（CNVs）的 85 例患者连续进行全外显子组测序（WES）。根据发病年龄和 ID 严重程度进行亚组分析。
遗传异常的总体诊断率为 33.3%（34/102），其中包括 50.0%的诊断性 CNVs 和 50.0%的诊断性 SNVs。尽管结果无统计学意义，但随着 ID 严重程度的增加和发病年龄的降低，诊断率有增加的趋势。出生后一年内发病的患者 SNV 的诊断率（25.0%（11/44））显著高于儿童期发病的患者（10.3%（6/58））（p=0.049），而儿童期发病的患者 CNVs 的诊断率（17.2%（10/58））高于 SNVs 的诊断率（10.3%（6/58））。SNP 微阵列检测到的最常见综合征性癫痫是 Angelman 综合征（n=4），其中 1 例经父源单亲二体性证实。同时，在散发病例中最常见的 SNVs 是 MECP2 突变（n=2）和 IQSEC2 突变（n=2）。
CMA 和 WES 都是一种针对遗传异质性疾病的有利的、无偏倚的方法。我们提出了一种针对儿科癫痫患者的有效诊断策略。对于出生后一年内发病的患者，推荐进行 WES 作为一线检测。然而，对于儿童期发病的癫痫患者，应考虑 SNP 微阵列作为一线检测。
