Non-Canonical Genetics of Hereditary Spherocytosis: A Clinical Case Report

A 7-year old male with Duane Retraction Syndrome and ADHD exhibited progressive lethargy, jaundice, and splenomegaly following multiple bouts upper respiratory infection symptoms. Lethargy persisted despite the resolution of URI, lethargy persisted. He had long-standing anemia (Hb 9-10g/dL), reticulocytosis (ARC 0.4-0.5 M cells/uL), elevated MCHC (34-36 g/dL) and spherocytes on blood smear lead to a clinical diagnosis of hereditary spherocytosis (HS). There is no family history of HS or other hemolytic anemias. Osmotic fragility was slightly increased and erythrocyte Band 3 expression by flow cytometry was reduced.

Although the clinical severity of HS is highly variable, patients typically present with hemolytic anemia and progressive splenomegaly at a frequency of 1:1000-2000 in the population. Loss-of-function mutations within 5 genes (ANK1, EPB42, SLC4A1, SPTB, and SPTA1) cause defects in cytoskeletal structure. The result is increased cell fragility and decreased cellular half-life due to weakened linkage of the erythrocyte plasma membrane to the cytoskeleton. Genetic testing of a limited panel of anemia-associated genes revealed only a heterozygous variant of unknown significance, EPB42 (chr15-43220725-C-T/ rs150530456/c.100+1G>A) affecting splicing of the minor transcript EPB42-206. In contrast, patients with complete loss of function of EPB42 exhibit autosomal recessive HS Type 5. We performed whole genome sequencing to identify other genetic changes that could contribute to the onset HS. Our patient has low polygenic risk scores for variants affect surrogate markers of HS-associated traits including changes in reticulocyte count and mean corpuscular hemoglobin concentration (MCHC). Finally, we nominate rare variants as potentially pathogenic based on the following criteria: low observed frequency in the population, the predicted effect of the variant on protein function, high levels of protein expression in mature erythrocytes, and the observed consequence of these variations on hematological parameters in the UK Biobank population. In the absence of a single, large-effect mutation, we propose an oligogenic composite of factors producing a mild clinical case of hereditary spherocytosis.

Heeney:Novartis: Consultancy, Current equity holder in publicly-traded company; Beam Therapeutics: Consultancy, Current equity holder in publicly-traded company; Pfizer: Consultancy, Current equity holder in publicly-traded company; Bluebird Bio: Consultancy; Blueprint Medicines: Consultancy; MiNA Therapeutics: Consultancy; Omeros: Consultancy; Abbott Labs: Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company; CRISPER Therapeutics: Current equity holder in publicly-traded company; Dianthus Therapeutics: Current equity holder in publicly-traded company; GE Healthcare: Current equity holder in publicly-traded company; Praxis: Current equity holder in publicly-traded company.