Respiratory ciliopathies including non-CF bronchiectasis

Gene: RPGR

Green List (high evidence)

Although few cases of PCD associated with RPGR variants have been published, the PCD diagnostic centre at University Hospital Southampton has diagnosed 5 cases of PCD where RPGR variants have been judged to be the cause of disease. 4 cases have stop gains in RPGR, 3 of whom had PCD diagnosed before eye disease and 1 of whom is an adult whose wet cough and rhinitis started in very early childhood before eye symptoms, but was diagnosed with RP before PCD (due to late referral for PCD rather than lack of symptoms). i.e. in all cases lung disease preceded eye disease. 1 case has a pathogenic missense mutation and is an adult who only has PCD, no eye disease. I am submitting this review as a researcher who works closely with the diagnostic service at UHS and Wessex Clinical Genetics Lab. The fact that RPGR has been downgraded to Amber was raised at our recent PCD genetics MDT and Prof Jane Lucas, who leads the diagnostic service at UHS asked me to submit a review to provide support for this gene being a 'Green' gene.

Created: 25 Jan 2021, 3:56 p.m. | Last Modified: 28 Jan 2021, 1 p.m.

Panel Version: 1.42

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
primary ciliary dyskinesia; non-CF bronchiectasis

Publications

• PMID: 16055928
• PMID: 22888088

Mode of pathogenicity
Other

Green List (high evidence)

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 8 Mar 2022, 11:15 a.m. | Last Modified: 8 Mar 2022, 11:15 a.m.

Panel Version: 1.55

This gene is associated with an appropriate phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green status at the next review.

Created: 2 Dec 2020, 1:57 p.m. | Last Modified: 2 Dec 2020, 1:57 p.m.

Panel Version: 1.29

Comment on publications: PMID: 22888088 and 14627685 are extra cases

Created: 2 Dec 2020, 1:56 p.m. | Last Modified: 2 Dec 2020, 1:56 p.m.

Panel Version: 1.29

Green List (high evidence)

Three unrelated families reported where males have sinorespiratory infections in addition to RP.

Created: 25 May 2020, 7:34 a.m. | Last Modified: 25 May 2020, 7:34 a.m.

Panel Version: 1.7

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Retinitis pigmentosa, X-linked, and sinorespiratory infections, with or without deafness, MIM# 300455

Publications

• 10094550
• 12920075
• 16055928

Variants in this GENE are reported as part of current diagnostic practice

I don't know

From GMS Respiratory Specialist Test Group webex call 18th Jan 2019; Agreed to keep Amber, not enough evidence to upgrade to Green. it was also felt that this might present with respiratory features before RP, however there are difficulties with coverage by NGS

Created: 21 Jan 2019, 5:24 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: RPGR; Suggested initial gene rating: Amber; Evidence for inclusion: XLRP can sometimes manifest with recurrent respiratory infections.; Evidence for exclusion: Syndromic, ocular manifestations main phenotype.; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): ORF15 difficult to sequence (repetitive region)

Created: 5 Dec 2018, 1:54 p.m.

Phenotype not clealy relevant to isomerism. See expert review from Hannah Mitchison for rationale for inclusion on PCD panel

Created: 4 Jul 2017, 7:25 a.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Retinitis pigmentosa 3

Comment on list classification: Discussed in group at GEL and agreed to include due to phenotypic overlap

Created: 10 May 2016, 9:57 a.m.

Red List (low evidence)

Gene should be deleted - causes a primary ciliopathy;PCD is a motile ciliopathy, likely unrelated at a functional level.

Created: 8 Dec 2015, 5:33 p.m.

Phenotypes
ciliopathies

Green List (high evidence)

UK mutations reported. OMIM does not seem to have picked up RPGR as an increasingly important cause of syndromic PCD syndromic cause. It is now clear that RPGR mutations can cause PCD+RP in a number of cases. (HM unpublished data and Bukowy-Bieryllo et al. Pediatr Pulmonol. 2013 Apr;48(4):352-63)

Created: 8 Dec 2015, 4:25 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Retinitis pigmentosa, X-linked, and sinorespiratory infections, with or without deafness

Publications

• PMID:16055928

Variants in this GENE are reported as part of current diagnostic practice