Submission Details

PIEZO1 (OMIM # 611184) was first identified as a mechanically activated cation channel in 2010 (PMID 20813920) and has been noted to be associated with autosomal recessive lymphatic malformation 6 and well as autosomal dominant dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema (DHS). Based upon current nomenclature in the literature, we have decided to refer to lymphatic malformation 6 as “generalized lymphatic dyplasia” or “GLD”. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found likely differences in molecular mechanisms between autosomal dominant and autosomal recessive disease and therefore these disease entities have been split into separate entities at this time. These two disease entities do show significant phenotypic overlap and therefore, these may later be lumped together if evidence permits. The split curation of autosomal dominant dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema has been curated separately.

Generalized lymphatic dysplasia (GLD) is a multigenic disorder characterized by primary systemic lymphedema in multiple body systems presenting prenatally or postnatally with pleural effusions, chylothoraces and/or pericardial effusions, ascites or limb edema. Facial cellulitis has been reported in multiple individuals with biallelic PIEZO1 variants and these GLD patients and unaffected carriers have consistently been found to have a mild, asymptomatic form of DHS with mild hemolysis, reduced erythrocyte osmotic resistance, or spherocytes and stomatocytes on blood smear.

In 2015, Fotiou et al (PMID: 26333996) performed exome sequencing on individuals from six unrelated families with generalized lymphatic dysplasia and identified homozygous or compound heterozygous variants in the PIEZO1 gene that segregated with disease, the majority of which were putative loss of function. Lukas et al in 2015 performed whole exome sequencing on a pair of sibs with GLD and identified compound heterozygosity for a PIEZO1 splice site variant c.3455+1G>A and a missense variant p.Glu2029Arg. Functional studies and expression data supported loss of function for both variants. Since that time, additional families with autosomal recessive GLD, with putative (truncating or splice site) or proven loss of function missense variants in PIEZO1 have been reported (PMIDs: 28518170, 30244526, 30930797, 28749478, 33227434, 31680349, 36453701).

Mechanotransduction is a critical regulator of lymphatic vascular development, and shear stress via fluid flow promotes lymphatic vessel growth and valve formation. Animal models support the role of PIEZO1 in the developing blood and lymphatic vasculature. Mice lacking PIEZO1 show embryonic lethality due to heart and angiogenic defects (PMID 25119035, 24958852). Endothelial or lymphatic endothelial specific PIEZO1 knockout showed PIEZO1 is required for lymphatic valve formation and restricting growth of lymphatic capillaries (PMID 30482854, 30676326, 35701867). In cultured blood and lymphatic endothelial cells, PIEZO1 knockdown is associated with reduced responses to flow observed as changes in the cytoskeleton and activation of downstream flow-responsive signaling pathways (PMID 25119035, 30482854, 35701867, 30676326). When overexpressed in 239T/HEK cells, truncation and some missense variants in PIEZO1 have demonstrated reduced protein expression and stability, failure to localize to the cell surface, and disrupted glycosylation which is associated with reduced channel activity in response to stretch or treatment with the PIEZO1 specific activator YODA (PMID: 34867393, 26387913, 32251670, 34489534). These studies all support a loss of function or dominant negative mechanism for several truncating, splice site or missense variants in affected individuals.

Substantial evidence supports this gene-disease relationship including case-level data and experimental data that support loss of PIEZO1 function in individuals with GLD. More evidence is available in the literature, but the maximum score for genetic and experimental evidence has been reached. In summary, there is definitive evidence to support the relationship between PIEZO1 and autosomal recessive generalized lymphatic dysplasia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Prenatal GCEP on the meeting date March 22nd, 2023 (SOP Version 9).