Background: Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism, recurrent infections, bleeding tendencies, and progressive neurological impairment. The syndrome is caused by mutations in the LYST gene, which plays a crucial role in lysosomal trafficking.

Objective: This study aims to characterize the molecular basis of CHS in a Tunisian patient by identifying mutations in the LYST gene and analyzing their impact on the protein function, correlating these findings with the patient's clinical presentation.

Methods: A comprehensive clinical assessment was conducted on the patient, followed by biochemical, hematological, and microbiological analyses. Additionally, LYST protein levels were quantified in the patient and their parents using an ELISA assay. Genomic DNA was extracted from the patient's blood, and Whole Exome Sequencing (WES) was performed to identify mutations in the LYST gene. The findings were confirmed through Sanger sequencing, and bioinformatic tools were employed to predict the functional consequences of the detected mutations.

Results: The patient presented with classical symptoms of CHS, including silver hair, hypopigmented skin, recurrent infections, and neurological decline, with an unusually late onset at 18 years. ELISA results demonstrated significantly reduced LYST levels in the patient (1.8 ng/ml) compared to heterozygous parents (7.8 ng/ml and 8.1 ng/ml) and controls (9.2 ng/ml). Genetic analysis revealed a novel homozygous deletion, c.10269_10275del (p.Gly3424SerfsTer15), in the LYST gene, leading to a frameshift mutation and premature termination of the protein. Bioinformatic analysis demonstrated that this mutation leads to the deletion of five out of sven WD40 repeats in the protein's C-terminal region, which are critical for protein-protein interactions and lysosomal trafficking.

Conclusion: The study identifies a novel LYST mutation in a Tunisian patient with CHS, expanding the spectrum of known genetic variants associated with the disease. The findings highlight the importance of genetic screening in populations with high consanguinity and underscore the need for targeted therapies to address the molecular defects in CHS.

Keywords: Chediak-Higashi syndrome; Genetic screening; In Silico analysis; Lysosomal trafficking regulator.

© 2025. The Author(s).

背景： Chediak-Higashi 综合征（CHS）是一种罕见的常染色体隐性遗传病，其特征包括眼皮肤白化症、反复感染、出血倾向和进行性的神经功能障碍。该综合征由LYST基因突变引起，LYST基因在溶酶体转运中起关键作用。

目的： 本研究旨在通过识别患者LYST基因中的突变并分析这些突变对蛋白质功能的影响，并将这些发现与患者的临床表现进行关联来表征突变型CHS的分子基础。

方法： 对患者进行了全面的临床评估，随后进行了生化、血液学和微生物学分析。此外，使用ELISA测定法量化了患者及其父母的LYST蛋白水平。从患者的血液中提取基因组DNA，并通过全外显子测序（WES）来识别LYST基因中的突变。利用Sanger测序确认发现的结果，并采用生物信息工具预测检测到的突变的功能后果。

结果： 患者表现出典型的CHS症状，包括银色头发、皮肤色素减退、反复感染和神经功能衰退，在18岁时出现异常晚发。ELISA结果显示患者的LYST水平显著降低（1.8 ng/ml），而杂合子父母的LYST水平分别为7.8 ng/ml 和 8.1 ng/ml，对照组为9.2 ng/ml。基因分析揭示了LYST基因中的一个新纯合缺失突变c.10269_10275del (p.Gly3424SerfsTer15)，导致蛋白质的移框突变和提前终止。生物信息学分析表明，这种突变在蛋白C端区域删除了七个WD40重复中的五个关键结构域，这些结构域对于蛋白质-蛋白质相互作用及溶酶体转运至关重要。

结论： 本研究在一名突尼斯CHS患者中发现了一种新的LYST基因变异，扩展了已知与该疾病相关的遗传变异范围。这项研究成果强调了对高度近亲繁殖人群中进行遗传筛查的重要性，并指出针对CHS分子缺陷的靶向治疗的需求。

关键词： Chediak-Higashi 综合征；遗传筛查；计算机模拟分析；溶酶体转运调节因子。