Pulmonary arterial hypertensionGene: GDF2
From GMS Respiratory Specialist Test Group webex call 18th Jan 2019 it was agreed there is enough evidence to rate this gene Green
Created: 21 Jan 2019, 10:04 p.m.
Initial gene list and info collated by Ian Berry Leeds Genetics Laboratory November 2018 on behalf of the GMS Respiratory specialist test group. Gene Symbol submitted: GDF2; Suggested initial gene rating: Green; Evidence for inclusion: HHT gene; some cases described w/ PAH; Evidence for exclusion: none given; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none given
Created: 6 Dec 2018, 2:01 p.m.
Comment on list classification: Change from Amber to Green. pers comm. Karyn Megy (NIHRRD-BR BRIDGE project), 9 independent unrelated families reported plus functional analysis- cells transfected with GDF2 variants in BRIDGE-PAH patients have reduced secretion of mature GDF2 protein. Note that BRIDGE-PAH patients reported had an enrichment of high impact variants in the gene; this was not a single gene analysis, but large scale gene analysis.
Created: 3 Sep 2018, 10:57 a.m.
Comment on publications: added publications to support upgrading of gene to Green. pers comm. Karyn Megy (NIHRRD-BR BRIDGE project), PMID: 26801773, one additional case (Spanish)
Created: 3 Sep 2018, 10:51 a.m.
More than three unrelated patients with variants in the novel PAH genes investigated. However, the authors recognise that additional validation of these findings will be required to be certain of causality and for subsequent clinical genetic counselling. They did not find examples of familial segregation with autosomal dominant heterozygous mutations in ATP13A3 or GDF2. Although it is possible that de novo mutation and incomplete penetrance of these mutations (similar to BMPR2 mutations) occurs, this will require additional collections of family members in the future to assess.
Created: 16 Apr 2018, 12:05 p.m.
From PMID: 29650961. Gräf et al (2018) describe a Case-Control study on pulmonary arterial hypertension (PAH) on 1048 cases and 6385 controls and the identification of 4 novel genes ATP13A3, AQP1, SOX17 and GDF2 causing this disease. Samples were sequenced with Whole Genome Sequencing. At first the authors detected samples with deleterious mutations in previously known PAH genes,including BMPR2, ACVRL1, ENG, KCNK3, SMAD9 and TBX14,and removed them from the further analysis to increase power of the statistic. For a distinct form of PAH, called pulmonary veno-occlusive disease or pulmonary capillary haemangiomatosis (PVOD/PCH) the authors showed significant association with mutations in EIF2AK4. The authors performed structural analysis for the novel genes ATP13A3, AQP1, SOX17 and GDF2, functional analysis on the GDF2 variants and expression analysis on ATP13A3, AQP1 and SOX17.
Created: 16 Apr 2018, 12:04 p.m.
Source NHS GMS was added to GDF2. Rating Changed from Green List (high evidence) to Green List (high evidence)
Gene: gdf2 has been classified as Green List (High Evidence).
Publications for gene: GDF2 were set to 29650961; 26801773
This gene has been classified as Amber List (Moderate Evidence).
Mode of inheritance for GDF2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
GDF2 was added to Pulmonary arterial hypertension panel. Sources: Literature
GDF2 was created by Louise Daugherty