부산대학교 도서관

IntroductionChediak-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 LYSTcause CHS. LYSTencodes the lysosomal trafficking regulator, a highly conserved 429 kDa cytoplasmic protein with an unknown function.MethodsTo 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 LYSTvariants. Additionally, we performed an extensive literature review to curate reported LYSTvariants and classified these novel and reported variants according to the American College of Medical Genetics/Association for Molecular Pathology variant interpretation guidelines.ResultsOur investigation unveiled 11 novel pathogenic LYSTvariants 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.ConclusionThe identification of novel pathogenic LYSTvariants and improvements in variant classification will provide earlier diagnoses and improved care to individuals with CHS.