Two Cases of Hemoglobinopathy Sc-like Retinopathy Associated With Coinheritance of Piezo1 Variants and Sickle Cell Trait
Year: 2026
Type: article
Study design: Case Report
Abstract: Background Sickle cell trait is a benign condition, which in the absence of other beta-hemoglobin variants is considered to not cause disease. However, variants in other genes involved in red blood cell (RBC) deformability and hydration content could lead to abnormal cell physiology, manifesting as clinical complications normally attributed to sickle cell disease. Here, we report two cases of unrelated patients with sickle cell trait (heterozygous variant HBB:NM_000518.5:c.20A>T) and features resembling Hemoglobinopathy SC disease, in the absence of other HBB variants. Cases Two men developed proliferative retinopathy at a young age, without traditional risk factors. In the work-up of the manifestation, both were shown to have compensated hemolysis with stomatocytes in peripheral blood, and iron overload in the absence of transfusion. Moreover, both patients presented splenomegaly and gallstones. Further investigation revealed HbAS pattern on electrophoresis and normal osmotic fragility test. A Laser-assisted Optical Rotational Cell Analyzer (LORRCA) test was performed, with RBC from both patients presenting a similar behavior, typical of dehydrated stomatocytosis (higher deformability at hyposmolar medium and decreased deformability at isosmolar and hyperosmolar media). Moreover, these LORRCA results, when compared to HbAS RBC, were more markedly different from that of HbAA controls, indicating the presence of an additional RBC factor interfering with their physiology. Given these results, both patients were investigated for mutations in the PIEZO1 gene. Patient 1 had PIEZO1 sequenced as part of a previously published work (Oliveira, 2020) with a heterozygous variant c.6041C>T:p.(Thr2014Ile), considered likely pathogenic. Importantly, his mother displayed the variant, but not HbAS, and presented features of dehydrated stomatocytosis, but did not have vascular complications. Patient 2 went through whole exome sequencing at the Centro Integrado de Doenças Genéticas e Raras (CIGEN), leading to the identification of the variant PIEZO1:c.5914T>A:p.(Phe1972Ile), deemed of uncertain significance. Discussion The cases presented here highlight the interplay of variants in two different genes leading to relevant clinical phenotypes which cannot be fully explained by the variants of each gene separately. Sickle cell trait is a benign disorder, but with relatively unexplored genetic modifiers that might lead to clinical manifestations. Conversely, dehydrated stomatocytosis, most commonly caused by gain of function (GoF) mutations in PIEZO1, can have a wide spectrum of hemolysis and iron overload, but small-vessel occlusion phenomena, like proliferative retinopathy, is not usually reported. Based on the clinical manifestations presented by the cases reported here, together with the functional and molecular studies, we propose that the combination of PIEZO1 GoF variants and sickle cell trait might lead to a retinopathy resembling that of Hemoglobinopathy SC disease. The rational behind this presentation is that the RBC dehydration, as a consequence of PIEZO1 mutations in hereditary xerocytosis, would lead to increased HbS concentration in RBC. This phenomenon would mimic the dehydration provoked by the presence of hemoglobin C, which leads to chronic hemolysis and increased blood viscosity. Finally, and in line with this rationale, both patients responded well to regular therapeutic phlebotomies as usually done in the management of HbSC disease.
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7223130934