Cytopenias and congenital anaemias
Gene: VPS45Comment on list classification: Changed status from Red to Green based on literature.Created: 22 Feb 2017, 10:30 a.m.
Comment on publications: (2 cases PMID:23738510,1 case PMID:23599270).
Both publications include consanguineous Palestinian families and although the publications do not refer to each other (the publications came out within the same month) there is no evidence to indicate they are related or not. However, there are still 3 unrelated families as PMID:23599270 asserts there is not a relationship between the 2 Palestinian families, who both had the Glu238Lys variant, and PMID:23738510, in addition to the Palestinian families (that may or may not be related to those in PMID:23599270) had one Moroccan family with a different causative variant Glu238Lys.
From PMID:23738510 : 5 affected children from 4 consanguineous Palestinian families with severe congenital neutropenia-5 had a homozygous missense mutation idenitified in the VPS45 gene Thr224Asn (c.671C→A; p.Thr224Asn).
Also, 2 affected children from 1 consanguineous Moroccan family who also had severe congenital neutropenia-5 had a homozygous missense mutation identified in the VPS45 gene but in Glu238Lys (c.712G→A; p.Glu238Lys).
Convincing functional evidence in PMID:23738510, VPS45 mutations were shown to cause this disease on the basis of the following findings: they fully segregated with the disease, were absent from 250 alleles of normal controls with the same genetic background and from published databases, caused structural alterations in VPS45, and were located in residues highly conserved among species. Furthermore, in both neutrophils and fibroblasts, the Thr224Asn mutation led to decreased VPS45 levels, affected proteins that interact with VPS45, impaired cell migration, and increased apoptosis. In addition, a zebrafish model with reduced vps45 protein had severe neutropenia, resembling that in the patients.
From PMID:23599270: 5 affected children from 2 unrelated consanguineous Palestinian families with severe congenital neutropenia-5 all had the same missense mutation idenitified in the VPS45 gene Thr224Asn (c.671C→A; p.Thr224Asn).Created: 22 Feb 2017, 10:24 a.m.
Comment on mode of pathogenicity: Only missense variants have been reported in OMIM.Created: 21 Feb 2017, 4:35 p.m.
Comment on phenotypes: added phenotypes/Synonyms from OMIM and OrphanetCreated: 21 Feb 2017, 3:42 p.m.
Comment on mode of inheritance: MOI from expert review and OMIMCreated: 21 Feb 2017, 3:38 p.m.
Promoted to V1 on 11 March 2017, after internal review and discussion with the clinical team.
This gene has been classified as Green List (High Evidence).
This gene has been classified as Green List (High Evidence).
Publications for VPS45 were set to 23738510; 23599270
Publications for VPS45 were set to 23738510;23599270
Mode of pathogenicity for VPS45 was changed to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Phenotypes for VPS45 were set to Neutropenia, severe congenital, 5, autosomal recessive, 615285; Congenital neutropenia-bone marrow fibrosis-nephromegaly syndrome; VPS45 deficiency; Severe congenital neutropenia
Phenotypes for VPS45 were set to Neutropenia, severe congenital, 5, autosomal recessive, 615285; Congenital neutropenia-bone marrow fibrosis-nephromegaly syndrome; VPS45 deficiency; Severe congenital neutropenia
Phenotypes for VPS45 were set to Neutropenia, severe congenital, 5, autosomal recessive,615285; Congenital neutropenia-bone marrow fibrosis-nephromegaly syndrome; VPS45 deficiency;Severe congenital neutropenia
Phenotypes for VPS45 were set to Neutropenia, severe congenital, 5, autosomal recessive,615285;Congenital neutropenia-bone marrow fibrosis-nephromegaly syndrome;VPS45 deficiency
Mode of inheritance for VPS45 was changed to BIALLELIC, autosomal or pseudoautosomal
VPS45 was created by LouiseD
VPS45 was added to Cytopaenias and congenital anaemiaspanel. Sources: Radboud University Medical Center, Nijmegen