Hemoglobin S/Chocowinity: A De Novo Compound Beta Globin Heterozygosity Resulting in Severe Sickle Cell Anemia
Authors: Fuh Beng R. , Clemons Kelli A , Khanchandhani Ashish A , Rivenbark Chelsea 
Published: December 2024

Sickle cell disease usually results from homozygosity of the HbS beta globin gene, HbS/beta thalassemia or from compound heterozygosity of the HbS gene and another mutation such as HbC. These mutations are usually inherited from parents who either have these conditions or are carriers of the traits.
Here we report a subtype of sickle cell disease that results from compound heterozygosity of the HbS trait and a de novo beta globin gene mutation, hemoglobin chocowinity, that results in severe sickle cell anemia.
Infant female was born to parents with known HbS trait in the mother and no known hemoglobinopathy in the father. Newborn screening showed Hemoglobin F and Hemoglobin S indicating sickle cell anemia. Paternity testing performed for other reasons confirmed paternity. Quantitative hemoglobin electrophoresis at 2 months of age showed HbF of 61.9%, HbS of 35.8%, and HbA2 of 2.3%. Blood counts in the following months showed worsening microcytosis so sickle cell beta thalassemia zero was suspected. Beta globin gene sequencing of the Beta 120 through the first two positions of 125 showed a mutation of the beta globin gene with deleted, CAGTGCCAA inserted HGVS: c.361_377delinsCAGTGCCAA, p.K121Qfs*17 Genomic: g.5246895_5246911delinsTTGGCACTG that has not been previously reported.
Hemoglobin electrophoresis via HPLC did not identify any unknown variant of hemoglobin indicating that this novel beta globin variant did not produce a stable hemoglobin. Bone marrow biopsy showed a grossly normocellular marrow with erythroid hyperplasia. Hemoglobin electrophoresis on the bone marrow did not identify any abnormal hemoglobin variant indicating that the gene product from this gene variant was not present even in early red blood cell progenitors. Testing for common alpha globin gene mutation was negative (normal).
Sickle cell trait was confirmed in the mother. Paternal testing showed normal blood counts with a normal hemoglobin, mean corpuscular volume, and other red blood cell indices. Paternal hemoglobin electrophoresis was normal with no findings to suggest beta thalassemia. Beta globin gene sequencing on the father showed normal wild type beta globin and specifically, the mutation identified in the patient was not identified in the father. This indicates that this is a de novo mutation in the patient.
The patient is now 3 years old and phenotypically, has high baseline hemolysis with severe baseline anemia. At baseline, hemoglobin is ~6g/dL, absolute reticulocyte counts of ~400k/uL, LDH ~1100U/L, Total bilirubin of ~2mg/dL. Severe sickle cell complications to date have included recurrent severe splenic sequestration for which splenectomy is planned and aplastic anemia. The patient was started on hydroxyurea with modest improvement in anemia and hemolysis indices.
In conclusion, we have identified a de novo mutation of the beta globin gene mutation, hemoglobin Chocowinity, which results in either a nonsense mutation or produces an extremely labile hemoglobin. Individuals who are compound heterozygous for this mutation and sickle cell trait, have a phenotype like hemoglobin beta thalassemia zero and have severe sickle cell anemia. Given the de novo nature of this mutation, close monitoring of the clinical course of this patient will be needed to further understand the clinical implications of this novel hemoglobinopathy.