Exome sequencing for diagnosis of congenital hemolytic anemia

Lamisse Mansour‐Hendili ,Valérie Ortonne,Benoît Funalot,Véronique Picard,Mylène Duplan,Stéphane Moutereau,Michel Bahuau,Nathalie Costedoat‐Chalumeau ,Orianne Wagner‐Ballon ,Ziad Mansour,Arnaud Petit,Abdelrazak Aissat,Marc Michel,Khaldoun Ghazal,Mehdi Sakka,Bouchra Badaoui,Corinne Guitton,Christine Gameiro,Serge Pissard,Pablo Bartolucci,Frédéric Galactéros

doi:10.1186/s13023-020-01425-5

Abstract

BackgroundCongenital hemolytic anemia constitutes a heterogeneous group of rare genetic disorders of red blood cells. Diagnosis is based on clinical data, family history and phenotypic testing, genetic analyses being usually performed as a late step. In this study, we explored 40 patients with congenital hemolytic anemia by whole exome sequencing: 20 patients with hereditary spherocytosis and 20 patients with unexplained hemolysis.ResultsA probable genetic cause of disease was identified in 82.5% of the patients (33/40): 100% of those with suspected hereditary spherocytosis (20/20) and 65% of those with unexplained hemolysis (13/20). We found that several patients carried genetic variations in more than one gene (3/20 in the hereditary spherocytosis group, 6/13 fully elucidated patients in the unexplained hemolysis group), giving a more accurate picture of the genetic complexity of congenital hemolytic anemia. In addition, whole exome sequencing allowed us to identify genetic variants in non-congenital hemolytic anemia genes that explained part of the phenotype in 3 patients.ConclusionThe rapid development of next generation sequencing has rendered the genetic study of these diseases much easier and cheaper. Whole exome sequencing in congenital hemolytic anemia could provide a more precise and quicker diagnosis, improve patients’ healthcare and probably has to be democratized notably for complex cases.

Highlights

Congenital hemolytic anemia constitutes a heterogeneous group of rare genetic disorders of red blood cells
Gallagher et al in 2019 [25] reported on a group of 24 recessive Hereditary spherocytosis (HS) patients explored by whole-exome sequencing (WES) and whole genome sequencing (WGS), all having mutations found in SPTA1
This work emphasizes the usefulness of WES in Congenital hemolytic anemia (CHA) in order to reach a right diagnosis for each patient

Summary

Introduction

Congenital hemolytic anemia constitutes a heterogeneous group of rare genetic disorders of red blood cells. Congenital hemolytic anemia (CHA) is a group of rare genetic disorders characterized by increased destruction of red blood cells (RBC) [1]. They result from corpuscular causes such as hemoglobin disorders, membrane diseases, RBC enzyme deficiencies or congenital dyserythropoietic anemia (CDA), or from extra-corpuscular causes such as Membrane disorders [2,3,4,5] include hereditary spherocytosis (HS, the most frequent cause in European population with nearly 1/2000 subjects affected, MIM 182900, 182,870, 270,970, 612,653, 612,690) [6]; hereditary elliptocytosis (HE, from 1/5000–1/10,000 in European population to 1/100 in West African populations, MIM 130600, 109,270, 611,804) [7]; hereditary pyropoïkilocytosis (HPP, MIM 266140), which is a rare and severe subtype of HE, and hereditary stomatocytosis, with a dehydrated form (incidence of 1/50,000 individuals, MIM 616689) and an overhydrated form Peripheral hemolysis can occur and misdiagnosis is often due to phenotypic overlap with other types of CHA [13, 14]

Results

Discussion

Conclusion