Gene Validity Curation

ELANE - neutropenia

Gene: ELANE (HGNC:3309)
Classification - 05/14/2020
Disease: neutropenia (MONDO_0001475)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hereditary Cancer EP
Evidence Summary: ELANE related neutropenia disorders include cyclic neutropenia (CyN) and severe congenital neutropenia (SCN). Cyclic neutropenia is usually diagnosed within the first year of life based on oscillation of neutrophils and fever with approximately 21 day periodicity. Congenital neutropenia is generally diagnosed right after birth and my present with omphalitis. Individuals with ELANE-related neutropenia are at risk of developing myelodysplasia syndrome (MDS) or acute myelogenous leukemia (AML). It is inherited in an autosomal dominant manner. Most reported pathogenic variants are missense, splicing defects, small in-frame deletions, frameshift deletions or premature stop codons with dominant negative effect. Full gene deletions leading to haploinsufficiency do not cause neutropenia (PMID: 31427279). At least 100 pathogenic variants have been reported in over 100 individuals from more than 40 families. This curation includes both familial and de novo missense, small deletion and splicing variants in individuals with CyN or SCN from 4 studies (PMID: 11001877, 10581030, 10581030 and 20803142). Three studies (PMID: 15657182, 31176364 and 28754797) were evaluated encompassing biochemical function, protein interaction, functional alteration from patients cells with different variants, and cell models expressing different variants further confirm the gene and disease validity. In summary, ELANE is definitively associated with CyN and SCN. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
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 2
3
3
Horwitz M et al. 1999 Dec (PMID:10581030); Liu Q et al. 2019 Jun 8 (PMID:31176364);
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 5
7.5
7
Dale DC et al. 2000 Oct 1 (PMID:11001877); Horwitz M et al. 1999 Dec (PMID:10581030); van de Vosse E et al. 2011 Feb (PMID:20803142);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 2.1 2.1  
Candidate gene sequencing 3.31 1
Horwitz M et al. 1999 Dec (PMID:10581030);
Exome/genome or all genes sequenced in linkage region 2.11 1
van de Vosse E et al. 2011 Feb (PMID:20803142);
Total Summed LOD Score 5.42    
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 4
2
2
Massullo P et al. 2005 May 1 (PMID:15657182);
Protein Interaction 0.5 0 - 2 1 0.5
Massullo P et al. 2005 May 1 (PMID:15657182);
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 2
2
2
Liu Q et al. 2019 Jun 8 (PMID:31176364);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2
Cell culture model 1 0 - 2 2 2
Makaryan V et al. 2017 Oct (PMID:28754797);
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) 6

 


 

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 6 18 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
05/14/2020
EXPERT CURATION (DATE)
Definitive
05/14/2020
EVIDENCE SUMMARY
ELANE related neutropenia disorders include cyclic neutropenia (CyN) and severe congenital neutropenia (SCN). Cyclic neutropenia is usually diagnosed within the first year of life based on oscillation of neutrophils and fever with approximately 21 day periodicity. Congenital neutropenia is generally diagnosed right after birth and my present with omphalitis. Individuals with ELANE-related neutropenia are at risk of developing myelodysplasia syndrome (MDS) or acute myelogenous leukemia (AML). It is inherited in an autosomal dominant manner. Most reported pathogenic variants are missense, splicing defects, small in-frame deletions, frameshift deletions or premature stop codons with dominant negative effect. Full gene deletions leading to haploinsufficiency do not cause neutropenia (PMID: 31427279). At least 100 pathogenic variants have been reported in over 100 individuals from more than 40 families. This curation includes both familial and de novo missense, small deletion and splicing variants in individuals with CyN or SCN from 4 studies (PMID: 11001877, 10581030, 10581030 and 20803142). Three studies (PMID: 15657182, 31176364 and 28754797) were evaluated encompassing biochemical function, protein interaction, functional alteration from patients cells with different variants, and cell models expressing different variants further confirm the gene and disease validity. In summary, ELANE is definitively associated with CyN and SCN. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.