INEFFECTIVE ERYTHROPOESIS DUE TO AN ALPHA SPECTRIN GENE DEFECT
(Abstract release date: 05/19/16)
EHA Library. Clark B. 06/09/16; 133016; E1467
Dr. Barnaby Clark
Contributions
Contributions
Abstract
Abstract: E1467
Type: Eposter Presentation
Background
Inherited red cell membrane disorders result from genetic changes within membrane and cytoskeletal proteins. When altered these proteins affect the deformability of the red cell and the stability of the membrane, which affects red cell function and results in a reduced red cell life span. Hereditary spherocytosis and elliptocytosis are relatively common with 1 in 2000 North Europeans being affected. Specific alpha spectrin gene variants, such as the low expression allele (LELY) have carrier frequencies of 20%, contributing to the high frequency that hereditary elliptocytosis is seen. The severity of the haemolytic anaemia is variable with some individuals unaware they are affected while others are lethal requiring in-utero transfusion for survival.We have identified two cases of particular interest. Both have a have a thalassaemia like syndrome with marked ineffective erythropoiesis due to mutations in the SPTA1 gene, coding for alpha spectrin. Case 1 presented with neonatal anaemia and liver failure, and is transfusion dependent. Case two presented with fetal anaemia and was treated with intrauterine transfusions; neonatally case two presented with hepatitis, anaemia and relative reticulocytopenia, and is also transfusion dependent.
Aims
To identify pathogenic variants in red cell membrane genes which account for ineffective erythropoiesis observed in the two patients.
Methods
Case 1 used whole exome sequencing of a nuclear family to identify the causative mutation while targeted sequencing using a focused red cell gene panel identified the pathogenic variant in the second case. Bespoke bioinformatics was used to analyse the data and call the variants.
Results
Case 1: Identified to be homozygous for the c. 7132C>T; p.Gln2378 * pathogenic variant in SPTA1 gene. Both parents were carriers and unaffected which is consistent with a recessive inheritance model.Case2. Identified to be homozygous for the c.2659C>T; p.Arg887* pathogenic variant in the SPTA1 gene. The individual was also homozygous for the SPTA1 c.[5572C>G; 6531-12C>T]; p.Leu1858Val low expression allele (Alpha Spectrin LELY). The parents were carriers of the pathogenic variant and also homozygous for the low expression allele. They did not have a clinically significant condition.
Conclusion
In both cases the affected individual was homozygous for a truncating mutation within SPTA1. The individual in case 1 was also homozygous for alpha spectin LELY and this may have contributed to the more severe phenotype, requiring intrauterine transfusion. We suggest, due to this novel mutation the red cells are too fragile to be released from the marrow, resulting in the phenotype of ineffective erythropoiesis (low reticulocytes) rather than haemolytic anemia, which is typically associated with alpha spectrin mutations.
Session topic: E-poster
Keyword(s): Red blood cell
Type: Eposter Presentation
Background
Inherited red cell membrane disorders result from genetic changes within membrane and cytoskeletal proteins. When altered these proteins affect the deformability of the red cell and the stability of the membrane, which affects red cell function and results in a reduced red cell life span. Hereditary spherocytosis and elliptocytosis are relatively common with 1 in 2000 North Europeans being affected. Specific alpha spectrin gene variants, such as the low expression allele (LELY) have carrier frequencies of 20%, contributing to the high frequency that hereditary elliptocytosis is seen. The severity of the haemolytic anaemia is variable with some individuals unaware they are affected while others are lethal requiring in-utero transfusion for survival.We have identified two cases of particular interest. Both have a have a thalassaemia like syndrome with marked ineffective erythropoiesis due to mutations in the SPTA1 gene, coding for alpha spectrin. Case 1 presented with neonatal anaemia and liver failure, and is transfusion dependent. Case two presented with fetal anaemia and was treated with intrauterine transfusions; neonatally case two presented with hepatitis, anaemia and relative reticulocytopenia, and is also transfusion dependent.
Aims
To identify pathogenic variants in red cell membrane genes which account for ineffective erythropoiesis observed in the two patients.
Methods
Case 1 used whole exome sequencing of a nuclear family to identify the causative mutation while targeted sequencing using a focused red cell gene panel identified the pathogenic variant in the second case. Bespoke bioinformatics was used to analyse the data and call the variants.
Results
Case 1: Identified to be homozygous for the c. 7132C>T; p.Gln2378 * pathogenic variant in SPTA1 gene. Both parents were carriers and unaffected which is consistent with a recessive inheritance model.Case2. Identified to be homozygous for the c.2659C>T; p.Arg887* pathogenic variant in the SPTA1 gene. The individual was also homozygous for the SPTA1 c.[5572C>G; 6531-12C>T]; p.Leu1858Val low expression allele (Alpha Spectrin LELY). The parents were carriers of the pathogenic variant and also homozygous for the low expression allele. They did not have a clinically significant condition.
Conclusion
In both cases the affected individual was homozygous for a truncating mutation within SPTA1. The individual in case 1 was also homozygous for alpha spectin LELY and this may have contributed to the more severe phenotype, requiring intrauterine transfusion. We suggest, due to this novel mutation the red cells are too fragile to be released from the marrow, resulting in the phenotype of ineffective erythropoiesis (low reticulocytes) rather than haemolytic anemia, which is typically associated with alpha spectrin mutations.
Session topic: E-poster
Keyword(s): Red blood cell
Abstract: E1467
Type: Eposter Presentation
Background
Inherited red cell membrane disorders result from genetic changes within membrane and cytoskeletal proteins. When altered these proteins affect the deformability of the red cell and the stability of the membrane, which affects red cell function and results in a reduced red cell life span. Hereditary spherocytosis and elliptocytosis are relatively common with 1 in 2000 North Europeans being affected. Specific alpha spectrin gene variants, such as the low expression allele (LELY) have carrier frequencies of 20%, contributing to the high frequency that hereditary elliptocytosis is seen. The severity of the haemolytic anaemia is variable with some individuals unaware they are affected while others are lethal requiring in-utero transfusion for survival.We have identified two cases of particular interest. Both have a have a thalassaemia like syndrome with marked ineffective erythropoiesis due to mutations in the SPTA1 gene, coding for alpha spectrin. Case 1 presented with neonatal anaemia and liver failure, and is transfusion dependent. Case two presented with fetal anaemia and was treated with intrauterine transfusions; neonatally case two presented with hepatitis, anaemia and relative reticulocytopenia, and is also transfusion dependent.
Aims
To identify pathogenic variants in red cell membrane genes which account for ineffective erythropoiesis observed in the two patients.
Methods
Case 1 used whole exome sequencing of a nuclear family to identify the causative mutation while targeted sequencing using a focused red cell gene panel identified the pathogenic variant in the second case. Bespoke bioinformatics was used to analyse the data and call the variants.
Results
Case 1: Identified to be homozygous for the c. 7132C>T; p.Gln2378 * pathogenic variant in SPTA1 gene. Both parents were carriers and unaffected which is consistent with a recessive inheritance model.Case2. Identified to be homozygous for the c.2659C>T; p.Arg887* pathogenic variant in the SPTA1 gene. The individual was also homozygous for the SPTA1 c.[5572C>G; 6531-12C>T]; p.Leu1858Val low expression allele (Alpha Spectrin LELY). The parents were carriers of the pathogenic variant and also homozygous for the low expression allele. They did not have a clinically significant condition.
Conclusion
In both cases the affected individual was homozygous for a truncating mutation within SPTA1. The individual in case 1 was also homozygous for alpha spectin LELY and this may have contributed to the more severe phenotype, requiring intrauterine transfusion. We suggest, due to this novel mutation the red cells are too fragile to be released from the marrow, resulting in the phenotype of ineffective erythropoiesis (low reticulocytes) rather than haemolytic anemia, which is typically associated with alpha spectrin mutations.
Session topic: E-poster
Keyword(s): Red blood cell
Type: Eposter Presentation
Background
Inherited red cell membrane disorders result from genetic changes within membrane and cytoskeletal proteins. When altered these proteins affect the deformability of the red cell and the stability of the membrane, which affects red cell function and results in a reduced red cell life span. Hereditary spherocytosis and elliptocytosis are relatively common with 1 in 2000 North Europeans being affected. Specific alpha spectrin gene variants, such as the low expression allele (LELY) have carrier frequencies of 20%, contributing to the high frequency that hereditary elliptocytosis is seen. The severity of the haemolytic anaemia is variable with some individuals unaware they are affected while others are lethal requiring in-utero transfusion for survival.We have identified two cases of particular interest. Both have a have a thalassaemia like syndrome with marked ineffective erythropoiesis due to mutations in the SPTA1 gene, coding for alpha spectrin. Case 1 presented with neonatal anaemia and liver failure, and is transfusion dependent. Case two presented with fetal anaemia and was treated with intrauterine transfusions; neonatally case two presented with hepatitis, anaemia and relative reticulocytopenia, and is also transfusion dependent.
Aims
To identify pathogenic variants in red cell membrane genes which account for ineffective erythropoiesis observed in the two patients.
Methods
Case 1 used whole exome sequencing of a nuclear family to identify the causative mutation while targeted sequencing using a focused red cell gene panel identified the pathogenic variant in the second case. Bespoke bioinformatics was used to analyse the data and call the variants.
Results
Case 1: Identified to be homozygous for the c. 7132C>T; p.Gln2378 * pathogenic variant in SPTA1 gene. Both parents were carriers and unaffected which is consistent with a recessive inheritance model.Case2. Identified to be homozygous for the c.2659C>T; p.Arg887* pathogenic variant in the SPTA1 gene. The individual was also homozygous for the SPTA1 c.[5572C>G; 6531-12C>T]; p.Leu1858Val low expression allele (Alpha Spectrin LELY). The parents were carriers of the pathogenic variant and also homozygous for the low expression allele. They did not have a clinically significant condition.
Conclusion
In both cases the affected individual was homozygous for a truncating mutation within SPTA1. The individual in case 1 was also homozygous for alpha spectin LELY and this may have contributed to the more severe phenotype, requiring intrauterine transfusion. We suggest, due to this novel mutation the red cells are too fragile to be released from the marrow, resulting in the phenotype of ineffective erythropoiesis (low reticulocytes) rather than haemolytic anemia, which is typically associated with alpha spectrin mutations.
Session topic: E-poster
Keyword(s): Red blood cell
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