Abstract：
BACKGROUND: Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterised by partial oculocutaneous albinism, a bleeding diathesis, immunological dysfunction and neurological impairment. Bi-allelic loss-of-function variants in LYST cause CHS. LYST encodes the lysosomal trafficking regulator, a highly conserved 429 kDa cytoplasmic protein with an unknown function.
METHODS: To further our understanding of the pathogenesis of CHS, we conducted clinical evaluations on individuals with CHS enrolled in our natural history study. Using genomic DNA Sanger sequencing, we identified novel pathogenic LYST variants. Additionally, we performed an extensive literature review to curate reported LYST variants and classified these novel and reported variants according to the American College of Medical Genetics/Association for Molecular Pathology variant interpretation guidelines.
RESULTS: Our investigation unveiled 11 novel pathogenic LYST variants in eight patients with a clinical diagnosis of CHS, substantiated by the presence of pathognomonic giant intracellular granules. From these novel variants, together with a comprehensive review of the literature, we compiled a total of 147 variants in LYST, including 61 frameshift variants (41%), 44 nonsense variants (30%), 23 missense variants (16%), 13 splice site variants or small genomic deletions for which the coding effect is unknown (9%), 5 in-frame variants (3%) and 1 start-loss variant (1%). Notably, a genotype-phenotype correlation emerged, whereby individuals harbouring at least one missense or in-frame variant generally resulted in milder disease, while those with two nonsense or frameshift variants generally had more severe disease.
CONCLUSIONS: The identification of novel pathogenic LYST variants and improvements in variant classification will provide earlier diagnoses and improved care to individuals with CHS.
METHODS: To further our understanding of the pathogenesis of CHS, we conducted clinical evaluations on individuals with CHS enrolled in our natural history study. Using genomic DNA Sanger sequencing, we identified novel pathogenic LYST variants. Additionally, we performed an extensive literature review to curate reported LYST variants and classified these novel and reported variants according to the American College of Medical Genetics/Association for Molecular Pathology variant interpretation guidelines.
RESULTS: Our investigation unveiled 11 novel pathogenic LYST variants in eight patients with a clinical diagnosis of CHS, substantiated by the presence of pathognomonic giant intracellular granules. From these novel variants, together with a comprehensive review of the literature, we compiled a total of 147 variants in LYST, including 61 frameshift variants (41%), 44 nonsense variants (30%), 23 missense variants (16%), 13 splice site variants or small genomic deletions for which the coding effect is unknown (9%), 5 in-frame variants (3%) and 1 start-loss variant (1%). Notably, a genotype-phenotype correlation emerged, whereby individuals harbouring at least one missense or in-frame variant generally resulted in milder disease, while those with two nonsense or frameshift variants generally had more severe disease.
CONCLUSIONS: The identification of novel pathogenic LYST variants and improvements in variant classification will provide earlier diagnoses and improved care to individuals with CHS.
摘要：
背景：Chediak-Higashi综合征（CHS）是一种罕见的常染色体隐性遗传疾病，以部分眼皮肤白化病为特征，流血的素质，免疫功能障碍和神经功能缺损。LYST中的双等位基因功能丧失变体引起CHS。LYST编码溶酶体运输调节因子,一种功能未知的高度保守的429kDa细胞质蛋白。
方法：为了进一步了解CHS的发病机制，我们对纳入自然史研究的CHS患者进行了临床评估.使用基因组DNASanger测序，我们鉴定了新的致病性LYST变体。此外,我们进行了广泛的文献综述,以筛选已报告的LYST变异体,并根据美国医学遗传学会/分子病理学变异体解释指南对这些新的和已报告的变异体进行分类.
结果：我们的调查揭示了8例临床诊断为CHS的患者的11种新型致病性LYST变异，由病理巨大的细胞内颗粒的存在证实。从这些新颖的变体中，以及对文献的全面回顾，我们在LYST中总共编译了147个变体，包括61个移码变体（41%），44个无义变体（30%），23个错觉变体(16%)，13个编码效应未知的剪接位点变异或小基因组缺失（9%），5个框内变体(3%)和1个起始丢失变体(1%)。值得注意的是,出现了基因型-表型相关性，因此，至少有一种错义或帧内变异的个体通常会导致较温和的疾病，而那些有两个无意义或移码变体的人通常患有更严重的疾病。
结论：新的致病性LYST变异的鉴定和变异分类的改进将为CHS患者提供更早的诊断和更好的护理。
方法：为了进一步了解CHS的发病机制，我们对纳入自然史研究的CHS患者进行了临床评估.使用基因组DNASanger测序，我们鉴定了新的致病性LYST变体。此外,我们进行了广泛的文献综述,以筛选已报告的LYST变异体,并根据美国医学遗传学会/分子病理学变异体解释指南对这些新的和已报告的变异体进行分类.
结果：我们的调查揭示了8例临床诊断为CHS的患者的11种新型致病性LYST变异，由病理巨大的细胞内颗粒的存在证实。从这些新颖的变体中，以及对文献的全面回顾，我们在LYST中总共编译了147个变体，包括61个移码变体（41%），44个无义变体（30%），23个错觉变体(16%)，13个编码效应未知的剪接位点变异或小基因组缺失（9%），5个框内变体(3%)和1个起始丢失变体(1%)。值得注意的是,出现了基因型-表型相关性，因此，至少有一种错义或帧内变异的个体通常会导致较温和的疾病，而那些有两个无意义或移码变体的人通常患有更严重的疾病。
结论：新的致病性LYST变异的鉴定和变异分类的改进将为CHS患者提供更早的诊断和更好的护理。
