PIEZO1-R1864H rare variant accounts for a genetic phenotype-modifier role in dehydrated hereditary stomatocytosis.

phenotype-modifier role in dehydrated hereditary stomatocytosis Dehydrated hereditary stomatocytosis (DHS) is an autosomal dominant hereditary hemolytic anemia characterized by erythrocyte dehydration due to loss of the cation content. Affected subjects exhibit highly variable clinical presentation, ranging from absence of clinical symptoms to lethal perinatal edema. They may present severe iron overload leading to hepatic transplantation, or life-threatening thromboembolic disease after splenectomy, thus making the diagnosis of this condition problematic.1 DHS results in two different forms: i) DHS1, the most frequent, is caused by mutations in PIEZO1, encoding a cation selective channel activated by mechanical force; ii) DHS2 due to an altered KCNN4 gene, encoding a Ca2+-sensitive (Gardos) channel.2-4 In particular, PIEZO1 is a large and highly polymorphic gene. Several electrophysiology studies demonstrated that the mutations cause a gain-of-function phenotype with delayed inactivation of the channel.5-10 We studied 7 DHS patients from two unrelated families (A-B) showing highly variable clinical expressivity and carrying the same new PIEZO1 mutation. We demonstrated that the presence of an additional de novo PIEZO1 rare missense variant in one of the 2 probands accounts for a more severe phenotype.