دانلود رایگان مقاله ارتباط ژنوتیپ فنوتیپ در الیپتوسیتوز و پیرو پویی کیلوسیتوزیس ارثی

Abstract

Hereditary elliptocytosis (HE) and hereditary pyropoikilocytosis (HPP) are heterogeneous red blood cell (RBC) membrane disorders that result from mutations in the genes encoding α-spectrin (SPTA1), β-spectrin (SPTB), or protein 4.1R (EPB41). The resulting defects alter the horizontal cytoskeletal associations and affect RBC membrane stability and deformability causing shortened RBC survival. The clinical diagnosis of HE and HPP relies on identifying characteristic RBC morphology on peripheral blood smear and specific membrane biomechanical properties using osmotic gradient ektacytometry. However, this phenotypic diagnosis may not be readily available in patients requiring frequent transfusions, and does not predict disease course or severity. Using Next-Generation sequencing, we identified the causative genetic mutations in fifteen patients with clinically suspected HE or HPP and correlated the identified mutations with the clinical phenotype and ektacytometry profile. In addition to identifying three novel mutations, gene sequencing confirmed and, when the RBC morphology was not evaluable, identified the diagnosis. Moreover, genotypic differences justified the phenotypic differences within families with HE/HPP.

4. Conclusion

Targeted sequencing using a Next-Generation sequencing platform is an efficient approach to identify or confirm the diagnosis of HE and HPP, especially in severe, transfusion-dependent cases where the RBC phenotype cannot be evaluated. Moreover, causative molecular diagnosis allows genotype-phenotype correlations in these heterogeneous disorders and may assist in prognosis discussions. When HPP is caused by an HE-causing mutation in SPTA1 in trans to αLELY, significant poikilocytosis and possible transfusion requirement is noted in infancy, typically with improvement of the phenotype to a mild hemolytic anemia later on. Heterozygous HE-causing mutations in both SPTB and SPTA1 demonstrated a similar HPP phenotype (significant in infancy with improvement after the first few months of life) in our case of patient #15 as well as in similar cases described previously [20,21]. In contrast, HPP due to biallelic SPTB mutations in the tetramerization domain appears to cause severe transfusion-dependent hemolytic anemia. Combining clinical data, ektacytometry, and family studies is essential in understanding the relevance of new genetic variants to the pathology of RBC cytoskeletal disorders, providing insights into the genotype-phenotype correlation, and improving the genetic counseling and clinical care for these patients and families.