Pulmonary arterial hypertensionGene: SOX17
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, 10:08 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: SOX17; Suggested initial gene rating: Green; Evidence for inclusion: PMID:29650961. Graf et al (2018); PMID:30044643 & 30029678, de novo & segregation cases, emerging gene at recent PAH conferences, see PanelApp.; 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: Changed from Amber to Green- Additional evidence from expert and publications from different studies supports a green rating. 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, 10:35 a.m.
Comment on publications: added publications to support upgrading of gene to Green. pers comm. Karyn Megy (NIHRRD-BR BRIDGE project). PMID:30029678 (suggest SOX17) and PMID: 30044643 (6 families).
Unpublished (from Nick Morrell – 2018-07): “In addition, the data have been validated in the US cohort as reported at the last world symposium on PAH”
Created: 3 Sep 2018, 10:26 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 SOX17 with the addition of familial co-segregation analyses is detailed in the publication. Familial segregation of a SOX17 nonsense mutation with PAH, based on independent screening of a BMPR2 mutation-negative family, demonstrated that the SOX17 variant arose de novo in the proband and was subsequently transmitted to 2 children who died of childhood onset strengthening the case for a causal role of SOX17 variants in PAH. Provide functional studies to demonstrate that SOX17 is expressed and/or localised to pulmonary vascular cells.
Created: 16 Apr 2018, 12:10 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, 12:10 p.m.
Source NHS GMS was added to SOX17. Rating Changed from Green List (high evidence) to Green List (high evidence)
Gene: sox17 has been classified as Green List (High Evidence).
Publications for gene: SOX17 were set to 29650961; 30029678; 30044643
Mode of inheritance for SOX17 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
This gene has been classified as Amber List (Moderate Evidence).
SOX17 was added to Pulmonary arterial hypertension panel. Sources: Literature
SOX17 was created by Louise Daugherty