ClinVar

In affected members of 2 French families with dehydrated hereditary stomatocytosis (DHS; 194380), previously reported by Grootenboer et al. (2000) (family 'VE') and Martinaud et al. (2008), respectively, and in 6 unrelated index DHS cases, Albuisson et al. (2013) identified heterozygosity for an in-frame 6-bp duplication (c.7479_7484dupGGAGCT) in exon 51 of the PIEZO1 gene, resulting in staggered in-frame duplication of the respective residues (leu2945_glu2496dup), which the authors designated E2496ELE. SNP analysis at the PIEZO1 gene showed that the duplication was carried by at least 4 different haplotypes, thus excluding an ancestral allele. The duplication segregated with disease in the 2 families and was not found in the 1000 Genomes, Exome Variant Server, or dbSNP (build 135) databases. However, E2496ELE was present in 2 of 600 healthy French controls, for a minor allele frequency of 0.0017; Albuisson et al. (2013) noted that 1 of the 2 positive healthy individuals had hyperkalemia in 1 of his blood tests, with no additional information available. Patch-clamp experiments in transfected HEK293 cells demonstrated a considerable increase in the inactivation time constant with the mutant compared to wildtype channel kinetics, indicating that E2496ELE represents a gain-of-function mutation.