Abstract：
OBJECTIVE: DYNC1H1 variants are involved on a disease spectrum from neuromuscular disorders to neurodevelopmental disorders. DYNC1H1-related epilepsy has been reported in small cohorts. We dissect the electroclinical features of 34 patients harboring de novo DYNC1H1 pathogenic variants, identify subphenotypes on the DYNC1H1-related epilepsy spectrum, and compare the genotype-phenotype correlations observed in our cohort with the literature.
METHODS: Patients harboring de novo DYNC1H1 pathogenic variants were recruited through international collaborations. Clinical data were retrospectively collected. Latent class analysis was performed to identify subphenotypes. Multivariable binary logistic regression analysis was applied to investigate the association with DYNC1H1 protein domains.
RESULTS: DYNC1H1-related epilepsy presented with infantile epileptic spasms syndrome (IESS) in 17 subjects (50%), and in 25% of these individuals the epileptic phenotype evolved into Lennox-Gastaut syndrome (LGS). In 12 patients (35%), focal onset epilepsy was defined. In two patients, the epileptic phenotype consisted of generalized myoclonic epilepsy, with a progressive phenotype in one individual harboring a frameshift variant. In approximately 60% of our cohort, seizures were drug-resistant. Malformations of cortical development were noticed in 79% of our patients, mostly on the lissencephaly-pachygyria spectrum, particularly with posterior predominance in a half of them. Midline and infratentorial abnormalities were additionally reported in 45% and 27% of subjects. We have identified three main classes of subphenotypes on the DYNC1H1-related epilepsy spectrum.
CONCLUSIONS: We propose a classification in which pathogenic de novo DYNC1H1 variants feature drug-resistant IESS in half of cases with potential evolution to LGS (Class 1), developmental and epileptic encephalopathy other than IESS and LGS (Class 2), or less severe focal or genetic generalized epilepsy including a progressive phenotype (Class 3). We observed an association between stalk domain variants and Class 1 phenotypes. The variants p.Arg309His and p.Arg1962His were common and associated with Class 1 subphenotype in our cohort. These findings may aid genetic counseling of patients with DYNC1H1-related epilepsy.
METHODS: Patients harboring de novo DYNC1H1 pathogenic variants were recruited through international collaborations. Clinical data were retrospectively collected. Latent class analysis was performed to identify subphenotypes. Multivariable binary logistic regression analysis was applied to investigate the association with DYNC1H1 protein domains.
RESULTS: DYNC1H1-related epilepsy presented with infantile epileptic spasms syndrome (IESS) in 17 subjects (50%), and in 25% of these individuals the epileptic phenotype evolved into Lennox-Gastaut syndrome (LGS). In 12 patients (35%), focal onset epilepsy was defined. In two patients, the epileptic phenotype consisted of generalized myoclonic epilepsy, with a progressive phenotype in one individual harboring a frameshift variant. In approximately 60% of our cohort, seizures were drug-resistant. Malformations of cortical development were noticed in 79% of our patients, mostly on the lissencephaly-pachygyria spectrum, particularly with posterior predominance in a half of them. Midline and infratentorial abnormalities were additionally reported in 45% and 27% of subjects. We have identified three main classes of subphenotypes on the DYNC1H1-related epilepsy spectrum.
CONCLUSIONS: We propose a classification in which pathogenic de novo DYNC1H1 variants feature drug-resistant IESS in half of cases with potential evolution to LGS (Class 1), developmental and epileptic encephalopathy other than IESS and LGS (Class 2), or less severe focal or genetic generalized epilepsy including a progressive phenotype (Class 3). We observed an association between stalk domain variants and Class 1 phenotypes. The variants p.Arg309His and p.Arg1962His were common and associated with Class 1 subphenotype in our cohort. These findings may aid genetic counseling of patients with DYNC1H1-related epilepsy.
摘要：
目的：DYNC1H1变异体涉及从神经肌肉障碍到神经发育障碍的疾病谱。DYNC1H1相关癫痫已在小群群报告。我们剖析了34例具有从头DYNC1H1致病变异的患者的临床电特征，确定DYNC1H1相关癫痫谱上的亚表型，并将我们队列中观察到的基因型-表型相关性与文献进行比较。
方法：通过国际合作招募具有新生DYNC1H1致病变异的患者。回顾性收集临床资料。进行潜在类别分析以鉴定亚表型。应用多变量二元逻辑回归分析来研究与DYNC1H1蛋白结构域的关联。
结果：DYNC1H1相关癫痫在17名受试者（50％）中表现为婴儿癫痫痉挛综合征（IESS），在这些个体中，有25％的癫痫表型演变成Lennox-Gastaut综合征（LGS）。在12名患者（35%）中，局灶性发作癫痫的定义。在两个病人中，癫痫表型包括广泛性肌阵挛性癫痫，在一个具有移码变体的个体中具有进行性表型。在我们大约60%的队列中，癫痫发作是耐药的。79%的患者出现皮质发育畸形,主要是在间脑-厚脑频谱上，特别是其中一半的后部优势。另外，在45％和27％的受试者中报告了中线和幕下异常。我们已经在DYNC1H1相关的癫痫谱上确定了三类主要的亚表型。
结论：我们提出了一种分类方法，其中致病性从头DYNC1H1变体在一半可能演变为LGS（1类）的病例中具有耐药性IESS，除IESS和LGS（2类）以外的发育性和癫痫性脑病，或较不严重的局灶性或遗传性全身性癫痫，包括进行性表型（3类）。我们观察到茎结构域变体和1类表型之间的关联。在我们的队列中，变体p.Arg309His和p.Arg1962His是常见的，并与1类亚表型相关。这些发现可能有助于DYNC1H1相关癫痫患者的遗传咨询。
方法：通过国际合作招募具有新生DYNC1H1致病变异的患者。回顾性收集临床资料。进行潜在类别分析以鉴定亚表型。应用多变量二元逻辑回归分析来研究与DYNC1H1蛋白结构域的关联。
结果：DYNC1H1相关癫痫在17名受试者（50％）中表现为婴儿癫痫痉挛综合征（IESS），在这些个体中，有25％的癫痫表型演变成Lennox-Gastaut综合征（LGS）。在12名患者（35%）中，局灶性发作癫痫的定义。在两个病人中，癫痫表型包括广泛性肌阵挛性癫痫，在一个具有移码变体的个体中具有进行性表型。在我们大约60%的队列中，癫痫发作是耐药的。79%的患者出现皮质发育畸形,主要是在间脑-厚脑频谱上，特别是其中一半的后部优势。另外，在45％和27％的受试者中报告了中线和幕下异常。我们已经在DYNC1H1相关的癫痫谱上确定了三类主要的亚表型。
结论：我们提出了一种分类方法，其中致病性从头DYNC1H1变体在一半可能演变为LGS（1类）的病例中具有耐药性IESS，除IESS和LGS（2类）以外的发育性和癫痫性脑病，或较不严重的局灶性或遗传性全身性癫痫，包括进行性表型（3类）。我们观察到茎结构域变体和1类表型之间的关联。在我们的队列中，变体p.Arg309His和p.Arg1962His是常见的，并与1类亚表型相关。这些发现可能有助于DYNC1H1相关癫痫患者的遗传咨询。
