LYST – Chediak-Higashi syndrome

Chediak-Higashi syndrome (CHS) is a rare autosomal recessive immunodeficiency disorder characterized by partial oculocutaneous albinism, recurrent infections, bleeding diathesis and progressive neurologic impairment. The causative gene, LYST, encodes the lysosomal trafficking regulator, a 3,801-amino-acid protein essential for normal granule formation in hematopoietic and pigment cells (PMID:9215679). Loss-of-function variants in LYST disrupt vesicular trafficking and result in pathognomonic giant granules in leukocytes and melanosomes.

Bi-allelic LYST mutations have been reported in over 100 unrelated patients across >30 families, including consanguineous kindreds and a case of maternal uniparental isodisomy (PMID:10482950). Segregation analysis in three affected Indian siblings confirmed homozygous LYST variants in two additional relatives (PMID:26622160). Overall, more than 147 variants have been curated, predominantly nonsense (n=44) and frameshift (n=61) alleles, consistent with a recessive loss-of-function mechanism.

The variant spectrum includes recurrent and private truncating alleles as well as rare missense changes. A commonly reported change, c.1540C>T (p.Arg514Ter), was identified in a compound heterozygous infant with absent NK-cell cytotoxicity prior to stem cell transplant (PMID:15896657). Missense and in-frame deletions are less frequent but correlate with milder, intermediate phenotypes in adolescent and adult presentations of CHS (PMID:11857544).

Functional studies in human cells and the murine beige model demonstrate that LYST deficiency leads to defective lysosomal trafficking, giant organelle formation, and impaired cytotoxic lymphocyte function (PMID:9215679). Rescue of immunologic defects by hematopoietic stem cell transplantation underscores the pathogenicity of truncating LYST variants. In silico splicing predictions and cDNA assays have verified splice-altering alleles resulting in premature termination (PMID:39858566).

No significant conflicting evidence disputing the LYST–CHS association has been reported. Phenotypic variability is mainly attributable to residual LYST function from hypomorphic alleles rather than alternative genetic causes. Late-onset CHS cases triggered by viral infection highlight the importance of environmental modifiers but do not weaken the core gene–disease link (PMID:39032214).

Collectively, robust genetic and functional evidence supports a Definitive LYST–Chediak-Higashi syndrome association. Early molecular diagnosis via LYST sequencing enables prompt hematopoietic stem cell transplantation, which remains the only curative therapy. Key take-home: consider LYST analysis in any patient with partial albinism, recurrent infections, and giant granules to guide life-saving interventions.

References

• Human molecular genetics • 1997 • Mutations in the Chediak-Higashi syndrome gene (CHS1) indicate requirement for the complete 3801 amino acid CHS protein PMID:9215679
• European journal of human genetics • 1999 • Chediak-Higashi syndrome associated with maternal uniparental isodisomy of chromosome 1 PMID:10482950
• International journal of trichology • 2015 • Silvery Hair with Speckled Dyspigmentation: Chediak-Higashi Syndrome in Three Indian Siblings PMID:26622160
• Molecular genetics and metabolism • 2005 • Two novel CHS1 (LYST) mutations: clinical correlations in an infant with Chediak-Higashi syndrome PMID:15896657
• American journal of medical genetics • 2002 • Apparent genotype-phenotype correlation in childhood, adolescent, and adult Chediak-Higashi syndrome PMID:11857544
• Blood cells, molecules & diseases • 2024 • Accelerated phase development in a late-onset adolescent Chediak-Higashi syndrome patient caused by compound novel LYST mutations in the setting of SARS-CoV-2 infection PMID:39032214
• Genes • 2024 • Novel LYST Variants Lead to Aberrant Splicing in a Patient with Chediak-Higashi Syndrome PMID:39858566
• Journal of medical genetics • 2024 • Spectrum of LYST mutations in Chediak-Higashi syndrome: a report of novel variants and a comprehensive review of the literature PMID:37788905

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