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

Introduction: 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 cause CHS. 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 variants. Additionally, we performed an extensive literature review to curate reported 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 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 , 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.

Conclusion: The identification of novel pathogenic variants and improvements in variant classification will provide earlier diagnoses and improved care to individuals with CHS.