拓展ARV1相关疾病超越经典发育性和癫痫性脑病的临床谱系

文献信息

中文摘要

目的： ARV1双等位基因致病变异经典上与发育性和癫痫性脑病38型（DEE38）相关，这是一种严重的婴儿期起病疾病，以耐药性癫痫、严重神经发育损害和早期死亡为特征。然而，新出现的证据提示其表型变异性更广。我们旨在通过回顾性病例系列和结构化文献综述，拓展ARV1相关疾病的临床和分子谱系。
方法： 我们回顾性识别了五个无亲缘关系的沙特阿拉伯家庭，这些家庭经全外显子组测序确认携带ARV1双等位基因致病性或可能致病性变异。我们回顾了临床、神经发育、神经生理、神经影像和多系统表现。我们进行了结构化文献综述，以整合既往报告的病例。
结果： 我们发现了显著的临床异质性，包括一个新发ARV1错义变异（c.214G>T；p.Asp72Tyr），尽管多种计算预测支持其有害效应，但根据ACMG/AMP标准，该变异仍被归类为意义未明变异。临床严重程度范围从伴有耐药性癫痫和早期死亡的严重发育性和癫痫性脑病，到较轻的非进展性神经发育表型，后者癫痫持续缓解并可长期存活至成年。携带相同纯合移码变异的家庭表现出显著不同的临床严重程度，支持不存在严格的基因型-表型相关性。多系统受累包括神经、心脏、骨骼、感觉、胃肠和泌尿生殖系统表现，代谢性拟表型导致了诊断延迟。
结论： 我们的研究结果表明，ARV1相关疾病代表一个广泛的多系统临床谱系，经典DEE38是其最严重的表现，而非其唯一表现。识别较轻表型、癫痫长期缓解和显著的表型变异性，对诊断、预后咨询和多学科长期监测具有重要意义。对于早发性癫痫伴多系统受累的患者，尤其是在近亲婚配人群中，应考虑早期基因组检测。

英文摘要

PURPOSE: Biallelic pathogenic variants in ARV1 are classically associated with developmental and epileptic encephalopathy-38 (DEE38), a severe infantile-onset disorder characterized by drug-resistant epilepsy, profound neurodevelopmental impairment, and early mortality. However, emerging evidence suggests broader phenotypic variability. We aimed to expand the clinical and molecular spectrum of ARV1-related disease through a retrospective case series and structured literature review.
METHODS: We retrospectively identified five unrelated Saudi Arabian families with biallelic pathogenic or likely pathogenic ARV1 variants confirmed by whole-exome sequencing. Clinical, neurodevelopmental, neurophysiological, neuroimaging, and multisystem findings were reviewed. A structured literature review was performed to integrate previously reported cases.
RESULTS: We identified marked clinical heterogeneity, including a novel ARV1 missense variant (c.214G>T; p.Asp72Tyr), which remains classified as a variant of uncertain significance according to ACMG/AMP criteria despite multiple computational predictions supporting a deleterious effect. Clinical severity ranged from severe developmental and epileptic encephalopathy with drug-resistant epilepsy and early mortality to milder static neurodevelopmental phenotypes with sustained seizure remission and long-term survival into adulthood. Families harboring the same homozygous frameshift variant exhibited markedly different clinical severity, supporting the absence of a strict genotype-phenotype correlation. Multisystem involvement included neurological, cardiac, skeletal, sensory, gastrointestinal, and genitourinary manifestations, and metabolic phenocopies contributed to diagnostic delays.
CONCLUSION: Our findings demonstrate that ARV1-related disease represents a broad multisystem clinical spectrum, with classical DEE38 representing its most severe presentation rather than its sole manifestation. Recognition of milder phenotypes, prolonged seizure remission, and marked phenotypic variability has important implications for diagnosis, prognostic counseling, and multidisciplinary long-term surveillance. Early genomic testing should be considered in patients with early-onset epilepsy and multisystem involvement, particularly in consanguineous populations.