Molecular surprises in evaluations of red cell disorders

Red cell disorders may present with overlapping clinical presentation and laboratory findings; in addition, complete phenotypic characterization of the patients' red cells is more challenging in the most severe cases, which are typically transfusion-dependent. The increasing availability of next-generation sequencing over the past 2 decades, initially with focused gene panels for certain disease groups, optimized to include the known coding and noncoding pathogenic variants for those diseases, has improved the accuracy and timeliness of diagnosis. The ongoing expansion to whole-exome and genome sequencing has been revealing unexpected, rare, overlooked, or previously unknown genetic disorders and expands our knowledge on the pathophysiology of known and novel human diseases. The vast information gained by genetic sequencing should still be checked against the phenotype to confirm agreement. A positive result does not always guarantee that the cause of the patient's symptoms has been identified; phenotype-genotype correlation is critical. In our era of targeted treatments and progress in gene therapy, utilization of genetic workup to improve the timing and precision of diagnosis is crucial to ensure that patients receive effective management, improving their outcome.