Pulmonary arterial hypertension

Gene: ATP13A3

Green List (high evidence)

Discussed with respiratory specialist group 18/01/19. Publication in press with multiple cases and functional data. Should be green on this panel.

Created: 20 Jan 2019, 6:09 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

data has been replicated in the US PAH Biobank

Created: 16 May 2019, 12:56 p.m.

Comment on mode of inheritance: changed MOI to reflect new data that a knock out mouse has a pulmonary vascular phenotype

Created: 16 May 2019, 12:55 p.m.

Comment on mode of inheritance: changed back MOI until confirmation

Created: 21 Jan 2019, 5:43 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: ATP13A3; Suggested initial gene rating: Amber; Evidence for inclusion: PMID: 29650961 Graf et al (2018), further evidence from BRIDGE study (see PanelApp); Evidence for exclusion: BRIDGE evidence not yet published; data in Graf et al. not yet convincing.; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none given

Created: 6 Dec 2018, 2:01 p.m.

Comment on list classification: Changed from Amber to Green- Additional evidence from expert, pers comm. Karyn Megy (NIHRRD-BR BRIDGE project) reports 6 independent cases with functional analysis showing that ATP13A3 knockout inhibit proliferation and increase apoptosis of endothelial cells –and it is known that apoptosis in those cells trigger PAH (PMID: 29650961). 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, 11:22 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. Functional studies demonstrate that ATP13A3 is expressed and/or localised to pulmonary vascular cells. Although unlike AQP1 and SOX17 it has never been studied in vascular cells, the publication provides functional data to show the impact of loss of ATP13A3 function in endothelial cells.

Created: 16 Apr 2018, 12:03 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, 12:03 p.m.