Baltar Federico, Simoes Camila, Garagorry Francisco, Graña Martín, Rodríguez Soledad, Haydée Aunchayna María, Tapié Alejandra, Cerisola Alfredo, González Gabriel, Naya Hugo, Spangenberg Lucía, Raggio Víctor
Unidad Académica de Neuropediatría, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
Departamento de Genética, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
Front Pediatr. 2024 May 1;12:1379254. doi: 10.3389/fped.2024.1379254. eCollection 2024.
Neuronal Ceroid Lipofuscinosis (NCL) disorders, recognized as the primary cause of childhood dementia globally, constitute a spectrum of genetic abnormalities. CLN8, a subtype within NCL, is characterized by cognitive decline, motor impairment, and visual deterioration. This study focuses on an atypical case with congenital onset and a remarkably slow disease progression.
Whole-genome sequencing at 30× coverage was employed as part of a national genomics program to investigate the genetic underpinnings of rare diseases. This genomic approach aimed to challenge established classifications (vLINCL and EPMR) and explore the presence of a continuous phenotypic spectrum associated with .
The whole-genome sequencing revealed two novel likely pathogenic mutations in the gene on chromosome 8p23.3. These mutations were not previously associated with CLN8-related NCL. Contrary to established classifications (vLINCL and EPMR), our findings suggest a continuous phenotypic spectrum associated with CLN8. Pathological subcellular markers further validated the genomic insights.
The identification of two previously undescribed likely pathogenic gene mutations challenges traditional classifications and highlights a more nuanced phenotypic spectrum associated with CLN8. Our findings underscore the significance of genetic modifiers and interactions with unrelated genes in shaping variable phenotypic outcomes. The inclusion of pathological subcellular markers further strengthens the validity of our genomic insights. This research enhances our understanding of disorders, emphasizing the need for comprehensive genomic analyses to elucidate the complexity of phenotypic presentations and guide tailored therapeutic strategies. The identification of new likely pathogenic mutations underscores the dynamic nature of -related NCL and the importance of individualized approaches to patient management.
神经元蜡样脂褐质沉积症（NCL）疾病是全球儿童痴呆的主要原因，由一系列基因异常构成。CLN8是NCL中的一种亚型，其特征为认知能力下降、运动障碍和视力减退。本研究聚焦于一例先天性起病且疾病进展极为缓慢的非典型病例。
作为一项国家基因组学计划的一部分，采用30倍覆盖度的全基因组测序来研究罕见病的遗传基础。这种基因组学方法旨在挑战既定分类（vLINCL和EPMR），并探索与……相关的连续表型谱的存在情况。
全基因组测序在8号染色体p23.3区域的……基因中发现了两个新的可能致病突变。这些突变以前未与CLN8相关的NCL联系在一起。与既定分类（vLINCL和EPMR）相反，我们的研究结果表明存在与CLN8相关的连续表型谱。病理性亚细胞标志物进一步验证了基因组学研究结果。
两个先前未描述的可能致病的……基因突变的发现挑战了传统分类，并突出了与CLN8相关的更细微的表型谱。我们的研究结果强调了遗传修饰因子以及与无关基因的相互作用在塑造可变表型结果方面的重要性。病理性亚细胞标志物的纳入进一步加强了我们基因组学研究结果的有效性。这项研究增进了我们对……疾病的理解，强调了进行全面基因组分析以阐明表型表现的复杂性并指导定制治疗策略的必要性。新的可能致病突变的发现突出了……相关NCL的动态性质以及患者个体化管理方法的重要性。
