Abstract：
OBJECTIVE: The APC2 gene, encoding adenomatous polyposis coli protein-2, is involved in cytoskeletal regulation in neurons responding to endogenous extracellular signals and plays an important role in brain development. Previously, the APC2 variants have been reported to be associated with cortical dysplasia and intellectual disability. This study aims to explore the association between APC2 variants and epilepsy.
METHODS: Whole-exome sequencing (WES) was performed in cases (trios) with epilepsies of unknown causes. The damaging effects of variants were predicted by protein modeling and in silico tools. Previously reported APC2 variants were reviewed to analyze the genotype-phenotype correlations.
RESULTS: Four pairs of compound heterozygous missense variants were identified in four unrelated patients with epilepsy without brain malformation/intellectual disability. All variants presented no or low allele frequencies in the controls. The missense variants were predicted to be damaging by silico tools, and affect hydrogen bonding with surrounding amino acids or decreased protein stability. Patients with variants that resulted in significant changes in protein stability exhibited more severe and intractable epilepsy, whereas patients with variants that had minor effect on protein stability exhibited relatively mild phenotypes. The previously reported APC2 variants in patients with complex cortical dysplasia with other brain malformations-10 (CDCBM10; MIM: 618677) were all truncating variants; in contrast, the variants identified in epilepsy in this study were all missense variants, suggesting a potential genotype-phenotype correlation.
CONCLUSIONS: This study suggests that APC2 is potentially associated with epilepsy without brain malformation/intellectual disability. The genotype-phenotype correlation helps to understand the underlying mechanisms of phenotypic heterogeneity.
METHODS: Whole-exome sequencing (WES) was performed in cases (trios) with epilepsies of unknown causes. The damaging effects of variants were predicted by protein modeling and in silico tools. Previously reported APC2 variants were reviewed to analyze the genotype-phenotype correlations.
RESULTS: Four pairs of compound heterozygous missense variants were identified in four unrelated patients with epilepsy without brain malformation/intellectual disability. All variants presented no or low allele frequencies in the controls. The missense variants were predicted to be damaging by silico tools, and affect hydrogen bonding with surrounding amino acids or decreased protein stability. Patients with variants that resulted in significant changes in protein stability exhibited more severe and intractable epilepsy, whereas patients with variants that had minor effect on protein stability exhibited relatively mild phenotypes. The previously reported APC2 variants in patients with complex cortical dysplasia with other brain malformations-10 (CDCBM10; MIM: 618677) were all truncating variants; in contrast, the variants identified in epilepsy in this study were all missense variants, suggesting a potential genotype-phenotype correlation.
CONCLUSIONS: This study suggests that APC2 is potentially associated with epilepsy without brain malformation/intellectual disability. The genotype-phenotype correlation helps to understand the underlying mechanisms of phenotypic heterogeneity.
摘要：
目的：APC2基因，编码腺瘤性息肉病coli-2蛋白，参与神经元对内源性细胞外信号的反应的细胞骨架调节，在脑发育中起重要作用。以前,据报道,APC2变异与皮质发育不良和智力障碍相关.本研究旨在探讨APC2变异与癫痫的关系。
方法：对原因不明的癫痫患者（三重奏组）进行全外显子组测序（WES）。通过蛋白质建模和计算机模拟工具预测变体的损伤效应。回顾了先前报道的APC2变体以分析基因型-表型相关性。
结果：在4名无脑畸形/智力障碍的非相关癫痫患者中发现了4对复合杂合错义变异。所有变体在对照中不呈现等位基因频率或呈现低等位基因频率。预测错误的变体会被硅质工具破坏，并影响与周围氨基酸的氢键或降低蛋白质的稳定性。变异导致蛋白质稳定性显著变化的患者表现出更严重和棘手的癫痫，而变异体对蛋白质稳定性影响较小的患者表现出相对温和的表型.先前报道的复杂皮质发育不良伴其他脑畸形-10（CDCBM10;MIM：618677）患者的APC2变异均为截短变异；相反，在这项研究中确定的癫痫变异都是错义变异，提示潜在的基因型-表型相关性。
结论：这项研究表明，APC2可能与没有脑畸形/智力障碍的癫痫有关。基因型-表型相关性有助于理解表型异质性的潜在机制。
方法：对原因不明的癫痫患者（三重奏组）进行全外显子组测序（WES）。通过蛋白质建模和计算机模拟工具预测变体的损伤效应。回顾了先前报道的APC2变体以分析基因型-表型相关性。
结果：在4名无脑畸形/智力障碍的非相关癫痫患者中发现了4对复合杂合错义变异。所有变体在对照中不呈现等位基因频率或呈现低等位基因频率。预测错误的变体会被硅质工具破坏，并影响与周围氨基酸的氢键或降低蛋白质的稳定性。变异导致蛋白质稳定性显著变化的患者表现出更严重和棘手的癫痫，而变异体对蛋白质稳定性影响较小的患者表现出相对温和的表型.先前报道的复杂皮质发育不良伴其他脑畸形-10（CDCBM10;MIM：618677）患者的APC2变异均为截短变异；相反，在这项研究中确定的癫痫变异都是错义变异，提示潜在的基因型-表型相关性。
结论：这项研究表明，APC2可能与没有脑畸形/智力障碍的癫痫有关。基因型-表型相关性有助于理解表型异质性的潜在机制。
