Pulmonary arterial hypertension

Gene: AQP1

I don't know

This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. The gene-disease association has recently been scored as "limited" by Clingen (https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_29eda804-13df-4fe9-bbb3-9494b11edc92-2021-01-11T145519.495Z) Therefore, this gene will remain Amber until further evidence/cases are reported.

Created: 16 Apr 2021, 10:44 a.m. | Last Modified: 16 Apr 2021, 10:44 a.m.

Panel Version: 2.10

Green List (high evidence)

There is evidence of association with high impact rare variants in AQP1 and PAH, and evidence of familial segregation.
A recurrent mutation R195Q, impacts on the water channel activity of AQP1.

Created: 22 Mar 2021, 1:47 p.m. | Last Modified: 22 Mar 2021, 1:47 p.m.

Panel Version: 2.9

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Pulmonary arterial hypertension

Publications

• PMID: 29650961

I don't know

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: AQP1; Suggested initial gene rating: Amber; Evidence for inclusion: PMID: 29650961. Graf et al (2018); Evidence for exclusion: Only three families, no convincing functional evidence.; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none given

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

Reviewed additional supplementary notes again, in light of upgrading SOX17. More than three unrelated families have been reported for AQP1 and co-segregation analysis was performed, no functional studies were undertaken and no other cohorts validating variants causing PAH have been published or announced at the world symposium on PAH, unlike SOX17. Kept Amber for now until further evidence.

Created: 3 Sep 2018, 11:43 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. Additional evidence of likely pathogenicity for AQP1 with the addition of familial co-segregation analyses is detailed in the publication. They identified familial segregation with rare AQP1 variants in 3 small families, adding support to the causal nature of these pathogenic variants in AQP1. Functional studies demonstrate that AQP1 is expressed and/or localised to pulmonary vascular cells.

Created: 16 Apr 2018, 12:16 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, 12:13 p.m.