SEVERE HEREDITARY HAEMOLYTIC ANAEMIA DUE TO THREE NOVEL SPTA1 MUTATIONS IN TWO COMPOUND HETEROZYGOUS UNRELATED PATIENTS.
Author(s): ,
Elena Krishnevskaya
Affiliations:
Red Cell Pathology and Haematopoietic Disorders Unit,Institute for Leukaemia Research Josep Carreras (IJC),Barcelona,Spain
,
Ines Hernandez Rodriguez
Affiliations:
Haematology-Haemotherapy Service,Catalan Institute of Oncology. Hospital Universitari Germans Trias i Pujol,Barcelona,Spain
,
Agueda Ancochea Serra
Affiliations:
Haematology-Haemotherapy Service,Catalan Institute of Oncology. Hospital Universitari Germans Trias i Pujol,Barcelona,Spain
,
Salvador Payán-Pernía
Affiliations:
Reference Centre (CSUR) for Hereditary Red Cell Pathology and Institut de Recerca,CSUR,Barcelona,Spain
,
Valeria Rizzuto
Affiliations:
Red Cell Pathology and Haematopoietic Disorders Unit,Institute for Leukaemia Research Josep Carreras (IJC),Barcelona,Spain
,
Marta Molero Magariño
Affiliations:
Haematology-Haemotherapy Service,Catalan Institute of Oncology. Hospital Universitari Germans Trias i Pujol,Barcelona,Spain;Red Cell Pathology and Haematopoietic Disorders Unit,Institute for Leukaemia Research Josep Carreras (IJC),Barcelona,Spain
Joan-Lluis Vives-Corrons
Affiliations:
Red Cell Pathology and Haematopoietic Disorders Unit,Institute for Leukaemia Research Josep Carreras (IJC),Barcelona,Spain;Department of Medicine,Universitat de Barcelona,Barcelona,Spain
EHA Library. Vives Corron J. Jun 15, 2019; 266821; PS1204
Joan-LLuis Vives Corron
Joan-LLuis Vives Corron
Contributions
Abstract

Abstract: PS1204

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background

Red blood cell (RBC) membrane defects are a cause of hereditary haemolytic anaemia (HHA) due to mutations in the genes that encode cytoskeletal proteins leading to a reduced cell deformity. Using next generation (NGS) and whole exome sequencing (WES), in two unrelated patients with HHA due to hereditary pyropoikilocytosis (HPP) and hereditary spherocytosis (HS), we have identified a complex set of mutations that affect SPTA1. Three are new: two due to an abnormal splicing and one to a micro election of chromosome 1

Aims

The main objective of our task is to provide a fast and efficient diagnosis of HHA using NGS and WES

Methods

NGS that includes a panel of 35 genes responsible for membranophaty (ANK1, EPB41, EPB42, SLC4A1, SPTB, SPTA1), haemoglobinopathy (HBA1, HBA2, HBB), enzymopathy (ADA, AK1, ALDOA, BPBM, CYB55, G6PD, GCLC, GPI, GSR, GSS, HK1, NT5C3A, PFKM, PGK1,) and CDA (CDAN1, C15orf41, SEC23B, KLF1, GATA1, KIF23). NGS and WES have been performed using an Illumina HiSeq2000 device

Results

 

Patient 1. A 40 year-old woman with HPP. CBC: Hb: 102g/l, MCV: 101fl and Retics: 260 x109/l. The study was performed after splenectomy and the OGE curve was typical of severe HS. NGS revealed two canonical splice-site mutations in SPTA1 gene: c.6842+2T>C and c.1599+2T>C. The c.6842+2T>C mutation is found in the lateral nucleation zone of a-spectrin with b-spectrin and produces an aberrant splicing eventually in 100% of the cases with a production of α-chains unsuitable for spectrin dimerization, and a decrease of binding to skeleton during the heterodimers assembly. The c.1599+2T>C mutation is in the zone of association of spectrin dimers leading to an aberrant splicing eventually in 100% of the cases and probably a change in the protein conformation that produces a breakage of tetramerisation and a loss of skeleton stability

Patient 2. A 2 year-old boy with HS. CBC: 72 g/l, MCV 95 fl and Retics:182 x109/l. Splenomegaly. The OGE curve was typical of moderate HS. The NGS analysis demonstrated a coinheritance for two different mutations in SPTA1 gene: n.158537345_158849273del and c.4339-99C>T. The n.158537345_158849273del, confirmed by WES, leads to a micro deletion of chromosome 1 that removes the entire SPTA1, leading to the absence of α‑spectrin. The c.4339-99C>T, also known as spectrin α-LEPRA, is an autosomic recessive mutation that causes a decrease of a-chain of 84%. Both SPTA1 gene mutations are autosomal recessive and their co-inheritance explains the severe HS

Conclusion

HPP and H are heterogeneous disorders of RBC membrane that can result from mutations in the genes encoding α-spectrin (SPTA1). The resulting defects an abnormal horizontal and/or vertical cytoskeletal associations affecting the stability and deformability of RBC membrane. The clinical diagnosis of HE and HS is based on the identification of the characteristic RBC morphology and specific membrane rheological abnormalities using the OGE. Here, two unrelated patients with severe elliptocytosis (HPP) and HS are described with the joint inheritance of a complex set of mutations (four in total) in the SPTA1 gene; three are new and one is the known as α-LEPRA. The correlation between genetic mutations NGS and EOG is discussed. Our study demonstrates the existence of complex interactions between SPTA1 gene mutations leading to severe haemolytic anaemia highlighting the usefulness of molecular diagnostics in patients with no identifiable family history of disorders of the erythrocyte cytoskeleton

Session topic: 28. Enzymopathies, membranopathies and other anemias

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