Complex Modes of Inheritance in Hereditary Red Blood Cell Disorders: A Case Series Study of 155 Patients.

Immacolata Andolfo,Achille Iolascon,Antonella Gambale,Roberta Russo,Stefania Martone,Gian Luca Forni,Roberta Marra,Vasiliki Papadopoulou,Mohsen Elalfy,Valeria Pinto,Magnus Göransson,Mathilde Gavillet,Barbara Eleni Rosato,Giovanna Tomaiuolo,Antonella Panarelli

doi:10.3390/genes12070958

Abstract

Hereditary erythrocytes disorders include a large group of conditions with heterogeneous molecular bases and phenotypes. We analyzed here a case series of 155 consecutive patients with clinical suspicion of hereditary erythrocyte defects referred to the Medical Genetics Unit from 2018 to 2020. All of the cases followed a diagnostic workflow based on a targeted next-generation sequencing panel of 86 genes causative of hereditary red blood cell defects. We obtained an overall diagnostic yield of 84% of the tested patients. Monogenic inheritance was seen for 69% (107/155), and multi-locus inheritance for 15% (23/155). PIEZO1 and SPTA1 were the most mutated loci. Accordingly, 16/23 patients with multi-locus inheritance showed dual molecular diagnosis of dehydrated hereditary stomatocytosis/xerocytosis and hereditary spherocytosis. These dual inheritance cases were fully characterized and were clinically indistinguishable from patients with hereditary spherocytosis. Additionally, their ektacytometry curves highlighted alterations of dual inheritance patients compared to both dehydrated hereditary stomatocytosis and hereditary spherocytosis. Our findings expand the genotypic spectrum of red blood cell disorders and indicate that multi-locus inheritance should be considered for analysis and counseling of these patients. Of note, the genetic testing was crucial for diagnosis of patients with a complex mode of inheritance.

Highlights

Hereditary anemias are a heterogeneous group of conditions that are characterized by complex genotype–phenotype correlations
We evaluated a large case series of 155 consecutive patients with different forms of hereditary anemias and erythrocytosis who were referred to the Medical Genetics
Among the 155 patients originally suspected of red blood cell defects, final diagnoses were reached for 130/155 (84%)

Summary

Introduction

Hereditary anemias are a heterogeneous group of conditions that are characterized by complex genotype–phenotype correlations. Genetic testing is used early in the diagnostic workflow of hereditary anemias, which removes the need for some of the specialized tests [8,9], especially when the clinical data for the patients are not informative, or when the patient is transfusion dependent. It remains a challenge to diagnose many hereditary anemia phenotypes according to phenotypic features and conventional diagnostic testing. In general clinical genetics setting, the diagnostic yield ranges from 38% to 87% of patients, depending on how many and which genes are included, and on the depth of the phenotypic assessment required [9]. A drawback of NGS-based genetic testing remains the data analysis, which includes several variants of unknown significance. Functional tests are crucial to assess the pathogenicity of new variants that are detected by NGS

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Discussion

Conclusion