GLUCOPHOSPHATE ISOMERASE DEFICIENCY IDENTIFIED BY NEXT-GENERATION SEQUENCING
Author(s): ,
Sona M Milan Vora
Affiliations:
Department of Haematology,Oxford University Hospitals,Oxford,United Kingdom
,
Melanie Proven
Affiliations:
Oxford Molecular Diagnostic Centre,Oxford University Hospitals,Oxford,United Kingdom
,
Ria Hipkiss
Affiliations:
Oxford Molecular Diagnostic Centre,Oxford University Hospitals,Oxford,United Kingdom
,
Pauline Ware
Affiliations:
Oxford Molecular Diagnostic Centre,Oxford University Hospitals,Oxford,United Kingdom
,
Kieran Howard
Affiliations:
Oxford Molecular Diagnostic Centre,Oxford University Hospitals,Oxford,United Kingdom
,
Helene Dreau
Affiliations:
Oxford Molecular Diagnostic Centre,Oxford University Hospitals,Oxford,United Kingdom
,
Susan Baird
Affiliations:
Department of Paediatric Haematology,Royal Hospital for Sick Children,Edinburgh,United Kingdom
,
Willem Ouwehand
Affiliations:
Department of Haematology,University of Cambridge,Cambridge,United Kingdom;Wellcome Sanger Institute,Cambridge,United Kingdom;NHS Blood and Transplant,Cambridge,United Kingdom
,
Karyn Megy
Affiliations:
NIHR BioResource,Cambridge University Hospitals NHS Foundation Trust,Cambridge,United Kingdom;Department of Haematology,University of Cambridge,Cambridge,United Kingdom
,
Kathleen E Stirrups
Affiliations:
NIHR BioResource,Cambridge University Hospitals NHS Foundation Trust,Cambridge,United Kingdom;Department of Haematology,University of Cambridge,Cambridge,United Kingdom
,
NIHR BioResource
Affiliations:
NIHR BioResource,Cambridge University Hospital NHS Foundation Trust,Cambridge,United Kingdom
,
Derek Lim
Affiliations:
West Midlands Regional Genetics Service, Clinical Genetics Department,Birmingham Women's and Children's Hospital NHS Foundation Trust,Birmingham,United Kingdom
,
Alice Norton
Affiliations:
Birmingham Women's and Children's Hospital NHS Foundation Trust,Birmingham,United Kingdom
,
Aswath Kumar
Affiliations:
Birmingham Women's and Children's Hospital NHS Foundation Trust,Birmingham,United Kingdom
,
Irene Roberts
Affiliations:
Weatherall Institute of Molecular Medicine,Oxford University,Oxford,United Kingdom
,
Mark Layton
Affiliations:
Department of Haematology,Imperial College London, Hammersmith Hospital,London,United Kingdom
Noemi BA Roy
Affiliations:
Department of Haematology,Oxford University Hospitals NHS Foundation Trust,Oxford,United Kingdom;Oxford Molecular Diagnostic Centre,Oxford University Hospitals NHS Foundation Trust,Oxford,United Kingdom;Weatherall Institute of Molecular Medicine,Oxford University,Oxford,United Kingdom
EHA Library. Vora S. Jun 14, 2019; 266234; PF434
Dr. Sona Vora
Dr. Sona Vora
Contributions
Abstract

Abstract: PF434

Type: Poster Presentation

Presentation during EHA24: On Friday, June 14, 2019 from 17:30 - 19:00

Location: Poster area

Background
Glucophosphate isomerase (GPI) deficiency is a rare erythroenzymopathy causing a defect in the glycolytic pathway. Prevalence is less than 1 in a million and inheritance is autosomal recessive. The diagnosis should be considered in those presenting with acute or chronic haemolysis, with a normal blood film and negative direct antibody screen. Molecular genetic analysis can be diagnostic and is confirmed functionally with GPI enzyme assay. 69 causal variants have been described in the GPI gene and over 50 clinical cases described.

Aims
To study cases of GPI deficiency identified by the Oxford Red Cell Panel (ORCP) and identify the clinical features that should alert clinicians to the possibility of this rare enzymopathy. 

Methods
We have studied 3 unrelated patients who presented with chronic non-spherocytic haemolytic anaemia (CNSHA) in infancy and were referred for the ORCP, a validated targeted next-generation sequencing (NGS) panel used to identify mutations in genes known to cause inherited anaemias.

Results
Proband 1 was born to consanguineous parents of Pakistani origin and referred at 5 months of age with unexplained neonatal anaemia, prolonged jaundice, and later seizures. ORCP showed homozygosity for a novel mutation, c.421G>A, predicted to result in the replacement of alanine with threonine at residue 141, (p.Ala141Thr) in exon 5 of GPI. This is a moderate change to a well conserved amino acid within the GPI protein. Her younger sister was also found to be homozygous for this mutation and died unexpectedly at 2 months of age.  Both parents were unaffected and confirmed to be heterozygous. 

Proband 2 was born to consanguineous parents of Kurdish ancestry and was referred at 13 months of age with transfusion-dependent CNSHA and jaundice. She was found to be homozygous for a novel GPI variant (c.397T>C, p.Cys133Arg), suspected to be pathogenic by in silico analysis due to a radical change in a highly conserved amino acid.  Functional verification is not possible due to transfusion dependence. Parental testing is underway.

Proband 3 was born to consanguineous parents of Pakistani origin and was referred aged 3 years with transfusion-dependent anaemia from birth, following severe neonatal anaemia and jaundice. The ORCP did not identify any mutations and the trio was submitted to the NIHR Bioresource whole genome sequencing programme.  Analysis revealed a homozygous variant c.605A>G (p.His202Arg), predicted to be pathogenic by in silico analysis and seen only rarely in public databases (<0.001%).  This variant was at a location which did not have any reads on the ORCP, explaining why it was not found by this method. Functional verification was inconclusive due to transfusion requirements. Both parents were found to have low GPI enzyme activity, consistent with a heterozygous state.

Conclusion
These cases illustrate the utility of NGS panels in identification of multiple rare inherited anaemias, including GPI deficiency. Testing should be considered for patients with transfusion dependent CNSHA for which no other cause has been identified. Neurological features and consanguinity in the parents may increase suspicion. Due to the rarity of the condition, clinicians may not specifically suspect GPI deficiency in these cases, but the upcoming reconfiguration of UK genomic services and centralisation of testing criteria should allow better access to molecular testing and improved detection of these rare conditions UK-wide.  The identification of specific molecular defects is helpful in providing parents with genetic counselling.

Session topic: 28. Enzymopathies, membranopathies and other anemias

Keyword(s): Hemolytic anemia, Inherited disease

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