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 dominant dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema as well as autosomal recessive lymphatic malformation 6.

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found likely differences in molecular mechanisms and therefore these disease entities have been split into separate disease 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 recessive lymphatic malformation 6 has been curated separately.

PIEZO1 was found to be associated with dehydrated hereditary stomatocystosis (DHS) in 2013 by Albuisson et al. DHS, also known as Hereditary Xerocytosis (HX), is an autosomal dominant disorder characterized by increased permeability of erythrocyte membranes to calcium resulting in subsequent loss of potassium and dehydration. Affected individuals may show mild to moderate compensated hemolytic anemia, pseudohyperkalemia, and blood films may show occasional stomatocytes. Mechanotransduction is also a critical regulator of lymphatic vascular development, and shear stress triggers signaling pathways that promote lymphatic vessel maturation and lymphatic valve formation. Affected individuals with transient perinatal edema or fetal hydrops have been observed in DHS families for many years (PMIDs: 11001917, 23479567, 23695678, 26333996, 28716860, 29673682, 30655378, 33027564, 32109669). Numerous variants have been reported in PIEZO1 in relation to DHS, the majority being missense mutations. The proposed molecular mechanism for PIEZO1 DHS is gain of function as many of the missense variants result in slower channel inactivation or reduced threshold of activation following stimulation of patient red blood cells or cells overexpressing missense variants. However, some missense variants have been shown to have a variety of effects on protein function including response to osmotic stress, membrane trafficking, or transcript and protein stability (PMIDs: 23695678, 28716860, 33478008, 30237269, 29210095, 34737711, 33973227, 26001275, 28619848, 26001274, 30930797). Therefore, the full spectrum of molecular mechanisms has not been fully resolved at this time.

Over 50 unique variants have been reported in individuals with DHS across numerous publications and only missense variants that reach likely pathogenic status based on ACMG criteria have been counted in this curation. Many additional variants of uncertain significance in affected individuals have been reported (Figure 2 PMID 36453701). Several recurrent variants, including the most frequently reported p.Arg2456His and p.L2495_E2496dup, but also p.Val598Met, p.Ala2020Thr, p.Thr2127Met and p.Arg2488 have been noted in at least three published reports in unrelated affected individuals. Segregation in multiple unrelated families has been demonstrated in the literature (including but not limited to PMIDs 23695678, 23581886, 32109669) reaching maximum scoring for segregation.

Substantial evidence supports this gene-disease relationship including case-level data, segregation, and experimental data that supports altered protein function for a selection of variants. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. In summary, there is definitive evidence to support the relationship between PIEZO1 and autosomal dominant dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema. 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).