Gene Validity Curation

LYST - Chediak-Higashi syndrome

Gene: LYST (HGNC:1968)
Classification - 05/27/2020
Disease: Chediak-Higashi syndrome (MONDO_0008963)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: 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).
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 7
14
12
Karim MA et al. 1997 Jul (PMID:9215679); Barbosa MD et al. 1997 Jul (PMID:9215680); Singh A et al. 2016 Mar (PMID:26499269); Jin Y et al. 2017 Feb 1 (PMID:28145517); Nagle DL et al. 1996 Nov (PMID:8896560);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
0.5
Sánchez-Guiu I et al. 2014 Jan (PMID:24112114); Song Y et al. 2020 Jan 6 (PMID:31906877);
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
0.5
0.5
Gil-Krzewska A et al. 2018 Sep (PMID:29241728);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 3 4 4
Runkel F et al. 2006 Mar (PMID:16518687); Anistoroaei R et al. 2013 Apr (PMID:22762706); Kunieda T et al. 1999 Dec (PMID:10594238);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 4.5

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 4.5 16.5 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
05/29/2020
EXPERT CURATION (DATE)
Definitive
05/27/2020
EVIDENCE SUMMARY
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).