Spectrum ofLYSTmutations in Chediak-Higashi syndrome: a report of novel variants and a comprehensive review of the literature

Abstract

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 inLYSTcause 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 pathogenicLYSTvariants. Additionally, we performed an extensive literature review to curate reportedLYSTvariants 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 pathogenicLYSTvariants 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 inLYST, 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 pathogenicLYSTvariants and improvements in variant classification will provide earlier diagnoses and improved care to individuals with CHS.