Institute of Neuroscience and Department of Neurology of the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China.
Department of Neurology, Maoming People's Hospital, Maoming, China.
Seizure. 2024 Mar;116:81-86. doi: 10.1016/j.seizure.2023.08.004. Epub 2023 Aug 9.
ATP6V1A variants have been identified in patients with highly variable phenotypes such as autosomal dominant epileptic encephalopathy and autosomal recessive cutis laxa. However, the mechanism underlying phenotype variation is unknown. We screened ATP6V1A variants in patients with epilepsy and analyzed the genotype-phenotype correlation to explain the mechanism underlying phenotypic variations.
We performed trio-based whole-exome sequencing in people with epilepsy without acquired causes. All previously reported ATP6V1A variants were systematically retrieved from the HGMD and PubMed databases.
Three novel de novo ATP6V1A variants, including c.749G>C/p.Gly250Ala, c.782A>G/p.Gln261Arg, and c.1103T>C/p.Met368Thr, were identified in three unrelated cases with childhood focal (partial) epilepsy. None of the variants were listed in any public population database and evaluated as likely pathogenic according to the criteria of the American College of Medical Genetics and Genomics (ACMG). All persons showed good responses to anti-seizure medication and psychomotor development was normal. Further analysis showed that monoallelic missense variants were associated with epilepsy with variable severity, whereas biallelic variants resulted in developmental abnormalities of multisystem that may result in early lethality.
Childhood focal epilepsy with favorable outcome was probably a novel phenotype of ATP6V1A. ATP6V1A variants are associated with a range of phenotypes that correlate with genotypes. The relationship between phenotype severity and the genotype (genetic impairment) of ATP6V1A variants helps explain the phenotypic variations.
ATP6V1A 变体已在具有高度可变表型的患者中被鉴定，例如常染色体显性遗传性癫痫性脑病和常染色体隐性皮肤松弛症。然而，表型变异的机制尚不清楚。我们在癫痫患者中筛选 ATP6V1A 变体，并分析基因型-表型相关性，以解释表型变异的机制。
我们对无获得性病因的癫痫患者进行了基于三亲的全外显子组测序。从 HGMD 和 PubMed 数据库中系统地检索了所有先前报道的 ATP6V1A 变体。
在三个无关的患有儿童局灶性（部分）癫痫的病例中发现了三个新的从头 ATP6V1A 变体，包括 c.749G>C/p.Gly250Ala、c.782A>G/p.Gln261Arg 和 c.1103T>C/p.Met368Thr。这些变体均未在任何公共人群数据库中列出，并根据美国医学遗传学与基因组学学院 (ACMG) 的标准评估为可能的致病性。所有患者均对抗癫痫药物反应良好，精神运动发育正常。进一步分析表明，单等位基因错义变体与严重程度可变的癫痫相关，而双等位基因变体导致多系统发育异常，可能导致早期致死。
具有良好预后的儿童局灶性癫痫可能是 ATP6V1A 的一种新表型。ATP6V1A 变体与一系列表型相关，与基因型相关。ATP6V1A 变体的表型严重程度与基因型（遗传损伤）之间的关系有助于解释表型变异。
