Genetic Landscape of Opsoclonus-Myoclonus-Ataxia Syndrome in Children

IF 2.1 3区医学 Q2 CLINICAL NEUROLOGY

Pediatric neurology Pub Date : 2025-09-04 DOI:10.1016/j.pediatrneurol.2025.08.019

Mark P. Gorman MD , In-Hee Lee PhD , Lauren M. Kerr BA , Kenneth D. Mandl MD, MPH , Sek Won Kong MD

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Abstract

Background

Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare neurological disorder, with involuntary rapid saccadic conjugate eye movements as one of characteristics, primarily affecting the cerebellum. While the exact pathogenesis remains unclear, genetic and autoimmune factors have been suggested to contribute to its development.

Methods

We enrolled patients diagnosed with OMAS before the age of 18 years at a pediatric neuroimmunology clinic in Boston, United States, using the 2004 Genoa Criteria. Whole genome sequencing was conducted for the patients and their biological parents in all cases, with one case including an unaffected twin sibling.

Results

De novo germline variants (DNVs) in probands were identified and validated and analyses of structural variants, recessive variants in neuroimmune-associated genes, and high-resolution human leukocyte antigen (HLA) typing were performed. Our study included 42 patients, 23 of whom had neuroblastoma. We found 12 confirmed DNVs in protein-coding regions in nine patients (29.0% of 31 from 30 trios and 1 quartet). Ten patients (23.8% of 42) had rare homozygous or compound heterozygous variants known to alter protein function, affecting 11 genes. Notably, the major histocompatibility complex, class II, DR beta 1 (HLA-DRB1) ∗01 allele was observed in 27 out of 84 (32.1%) alleles in the patients, significantly higher than that in the general population (chi-square test, P < 0.0001). In one case, a potential genetic modifier of OMAS with severe cerebellar atrophy was identified, associated with a protein-truncating DNV in the CACNA2D2 gene.

Conclusions

This first genome sequencing study reveals potential genetic contributors to OMAS, implicating polygenic predisposition—with HLA-DRB1∗01 as a possible factor—combined with nongenetic risk factors like neuroblastoma.

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儿童眼阵挛-肌阵挛-共济失调综合征的遗传图谱

背景：大阵挛-肌阵挛-共济失调综合征（OMAS）是一种罕见的神经系统疾病，其特征之一是不自主的快速跃迁共轭眼运动，主要影响小脑。虽然确切的发病机制尚不清楚，但遗传和自身免疫因素已被认为有助于其发展。方法：我们在美国波士顿的一家儿科神经免疫学诊所招募了18岁前诊断为OMAS的患者，使用2004年热那亚标准。对所有病例的患者及其亲生父母进行了全基因组测序，其中一例包括未受影响的双胞胎兄弟姐妹。结果对先证者的新生种系变异（dnv）进行了鉴定和验证，并对结构变异、神经免疫相关基因的隐性变异和高分辨率人类白细胞抗原（HLA）分型进行了分析。我们的研究包括42例患者，其中23例患有神经母细胞瘤。我们在9例患者的蛋白质编码区发现了12个确认的dnv（来自30例三重奏组和1例四重奏组的31例中的29.0%）。10例患者（42例中的23.8%）有罕见的纯合或复合杂合变异，已知会改变蛋白质功能，影响11个基因。值得注意的是，在患者的84个等位基因中，有27个（32.1%）存在主要的组织相容性复合体II类DR β 1 (HLA-DRB1)∗01等位基因，显著高于一般人群（卡方检验，P < 0.0001）。在一个病例中，发现了严重小脑萎缩的OMAS的潜在遗传修饰因子，与CACNA2D2基因中的蛋白截断DNV相关。这项首次基因组测序研究揭示了OMAS的潜在遗传因素，暗示多基因易感性- HLA-DRB1 * 01可能是一个因素-结合非遗传危险因素，如神经母细胞瘤。

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来源期刊

Pediatric neurology 医学-临床神经学

CiteScore

4.80

自引率

2.60%

发文量

176

审稿时长

78 days

期刊介绍： Pediatric Neurology publishes timely peer-reviewed clinical and research articles covering all aspects of the developing nervous system. Pediatric Neurology features up-to-the-minute publication of the latest advances in the diagnosis, management, and treatment of pediatric neurologic disorders. The journal''s editor, E. Steve Roach, in conjunction with the team of Associate Editors, heads an internationally recognized editorial board, ensuring the most authoritative and extensive coverage of the field. Among the topics covered are: epilepsy, mitochondrial diseases, congenital malformations, chromosomopathies, peripheral neuropathies, perinatal and childhood stroke, cerebral palsy, as well as other diseases affecting the developing nervous system.