Submission Details

LYST was first reported in relation to Autosomal Recessive Chediak-Higahsi syndrome in 1996 (Nagle et al, PMID: 8896560). At least 50 unique variants, including nonsense, frameshift, missense, deletion and duplication variants have been reported to cause disease in humans, in ClinVar. The exact function of the LYST is not completely understood, but is involved in regulating intracellular protein trafficking in endosomes. Chediak-Higahsi syndrome is characterized by partial oculocutaneous albinism, immunodeficiency, and a mild bleeding tendency. Some individuals develop the accelerated phase, or hemophagocytic lymphohistiocytosis, which can be life-threatening (Toro et al, GeneReviews). Evidence supporting this gene-disease relationship includes case-level data and experimental data.

Summary of Case Level Data: 12 Points Variants in this gene have been reported in at least 9 probands in 7 publications (PMIDs: 8896560, 9215680, 31906877, 9215679, 26499269, 24112114, 28145517). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.

The mechanism for disease is biallelic loss of function (Ajitkumar & Ramphul, 2019).

Summary of Experimental Data: 4.5 Points This gene-disease association is supported by a number of animal models and in vitro functional assays. Chediak-Higashi syndrome arises spontaneously in many animals, including the beige/grey mice, American mink and Japanese black cattle, due to a natural defect in the Lyst gene (PMID: 16518687, 22762706, 10594238, 10690356). CRISPR-generated LYST-deficient NK cells recapitulate a cellular phenotype that is consistent with that seen in humans (PMID: 29241728).

In summary, LYST is definitively associated with Autosomal Recessive Chediak-Higahsi syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hemostasis/Thrombosis GCEP on May 29, 2020 (SOP Version 7).

LYST was first reported in relation to Autosomal Recessive Chediak-Higahsi syndrome in 1996 (Nagle et al, PMID: 8896560). At least 50 unique variants, including nonsense, frameshift, missense, deletion and duplication variants have been reported to cause disease in humans, in ClinVar. The exact function of the LYST is not completely understood, but is involved in regulating intracellular protein trafficking in endosomes. Chediak-Higahsi syndrome is characterized by partial oculocutaneous albinism, immunodeficiency, and a mild bleeding tendency. Some individuals develop the accelerated phase, or hemophagocytic lymphohistiocytosis, which can be life-threatening (Toro et al, GeneReviews). Evidence supporting this gene-disease relationship includes case-level data and experimental data.

Summary of Case Level Data: 12 Points Variants in this gene have been reported in at least 9 probands in 7 publications (PMIDs: 8896560, 9215680, 31906877, 9215679, 26499269, 24112114, 28145517). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.

The mechanism for disease is biallelic loss of function (Ajitkumar & Ramphul, 2019).

Summary of Experimental Data: 4.5 Points This gene-disease association is supported by a number of animal models and in vitro functional assays. Chediak-Higashi syndrome arises spontaneously in many animals, including the beige/grey mice, American mink and Japanese black cattle, due to a natural defect in the Lyst gene (PMID: 16518687, 22762706, 10594238, 10690356). CRISPR-generated LYST-deficient NK cells recapitulate a cellular phenotype that is consistent with that seen in humans (PMID: 29241728).

In summary, LYST is definitively associated with Autosomal Recessive Chediak-Higahsi syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hemostasis/Thrombosis GCEP on May 29, 2020 (SOP Version 7).

Due to the overlapping phenotype of Chediak-Higashi Syndrome (CHS) with immunodeficiency and immune dysregulation, the PIRD GCEP has provided an addendum to this gene curation: A large proportion of CHS patients (~85-90%) develop hyperinflammatory (or immune dysregulation) manifestations categorized ashemophagocytic lymphohistiocytosis. There are a subset of patients who develop attenuated disease, which is regarded as atypical CHS. LYST is a 429 kDa protein with several distinct domains involved in several aspects of vesicle trafficking. Patients with CHS have giant lysosomes or lysosome-related organelles in many cell subsets. NK cells in CHS patients have aberrant morphology and function, including lytic granule polarization and size among other features that severely compromise NK cell cytotoxicity. However, cytokine secretion in NK cells does not appear to be affected. Therefore, LYST appears to be important for regulated exocytosis but not for constitutive exocytosis, which supports the development of IFN-gamma-driven hyperinflammatory syndromes in CHS patients, in response to a trigger or stimulus (e.g. viral infection). In mouse models, it has been shown that Lyst regulates TLR3 and TLR4-mediated proinflammatory responses with increased susceptibility to bacterial infections. In patients with hypomorphic LYST variants, the attenuated disease is associated with subclinical or no immunodeficiency but rather a progressive, neurodegenerative phenotype in early adulthood. (PMIDs: 26478006; 27881733; https://doi.org/10.1186/1750-1172-8-46)