Hereditary Erythrocytosis

Gene: PIEZO1

I don't know

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains Amber.

GMS reviewers note that it is a very polymorphic gene that will impose a substantial analysis burden. Publication identifies 4 "possibly" causative mutations and stresses the importance of electrophysiological assessment of variants, which is not always easy to arrange.

Created: 1 Feb 2023, 8:29 a.m. | Last Modified: 1 Feb 2023, 8:34 a.m.

Panel Version: 1.46

Green List (high evidence)

Comment on list classification: New association with this phenotype identified by external reviewer, Dmitrijs Rots. Rating Amber but there is sufficient evidence to promote this gene to Green at the next GMS panel update.

Created: 4 Jan 2022, 2:05 p.m. | Last Modified: 4 Jan 2022, 2:05 p.m.

Panel Version: 1.44

Well-established association of PIEZO1 variants with hereditary xerocytosis (MIM# 194380) which typically is accompanied by haemolytic anaemia. However, a small group of patients have been found with absent or well-compensated haemolysis but instead with erythrocytosis (PMID: 33181827, 31298594, 30655378).

Inclusion on this panel discussed with Helen Brittain (Genomics England Clinical Team) who states: "The mechanism is not exactly clear, in particular as to why some present with the xerocytosis where as others have erythrocytosis / mild haemolytic jaundice. It does appear there are sufficient cases with a phenotype that is relevant for this panel and I can see a number of different missense variants reported. On that basis it would meet the criteria for green rating. Suspected GOF."

Created: 4 Jan 2022, 2:03 p.m. | Last Modified: 4 Jan 2022, 2:03 p.m.

Panel Version: 1.43

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• 33181827
• 31298594
• 30655378

Green List (high evidence)

Pathogenic variants (gain-of-function missense) in the PIEZO1 has been previously identified as a cause of hereditary xerocytosis. Recently, it has been Identified that similar (likely) pathogenic GoF missense variants likely causes erythrocytosis in 5 individuals. Functional analysis confirms pathogenicity of the variants. Patients also displayed features of hereditary xerocytosis.
Sources: Literature

Created: 30 Nov 2021, 9:26 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Erythrocytosis

Publications

• PMID: 33181827

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments