P1531: HETEROGENEITY OF DISEASE-CAUSING GENOTYPES BETWEEN FAMILIES WITH HEREDITARY SPHEROCYTOSIS: A SINGLE-CENTER COHORT STUDY

Abstract

Background: Hereditary spherocytosis (HS) is a phenotypically and genetically heterogeneous disease, in which erythrocytes are unable to maintain their normal biconcave shape due to genetic mutations in membrane/cytoskeletal proteins that play a role in structural morphologic stability. Recent progress in genomic analyses technologies has helped to shed light on the complexity of genotype/phenotype correlations within this orphan hemolytic red blood cell disorder. Aims: In this retrospective investigation, we aim to investigate the genotype-phenotype correlation based on the clinical severity of the disease and the gene-wise predicted pathogenicity comparison. Furthermore, we want to highlight the importance of next generation sequencing (NGS) technologies in the diagnosis of HS. Methods: We provide the results of a single-center study in Austria on a total of 69 patients (core group, N=35; affected family members, N=34) with HS, focusing on NGS results (both exome and panel sequencing), ancestry, laboratory findings, clinics, as well as genotype-phenotype correlations. Results: A pathogenic (N=59/69; core group, N=29/35) or likely pathogenic variant (N=6/69; core group N=3/35) was identified in 94% (core group 91%) of the patients, including 18 novel variants. Variants in ANK1 (46%; European ancestry 37%, non-European 9%) were most encountered, followed by SPTB (31%, all European) and SLC4A1 (14%; European 11%, non-European 3%). In three patients (9%, all European) we were unable to identify the genetic cause unequivocally. Except for a heterozygous intronic ANK1 c.1504-9G>A variant, which was identified in two unrelated European families, there was no overlap on causative variants. The majority of mutations (N=25; 81%) were of high impact and include frameshifts, N=14 (45%); nonsense, N=8 (26%); CNVs, N=2 (6%) and splice-site variants, N=1 (3%). Sufficient data for phenotype-genotype correlation testing were available for 56 patients (core group, N=35), and phenotypes were milder in the patients with SLC4A1 variants. Patients with ANK1 and SPTB variants had comparable phenotypes. Summary/Conclusion: To our knowledge, this is the first study describing genomics (N=69) and genotype-phenotype correlation (N=56) in patients with HS in Central-Europe. We were able to identify causative variants in 94% of the 69 patients, including atypical disease-causing genetic findings such as intronic and CNV mutations. This evidenced the compelling need of a combination of standardized NGS analysis and clinical deep investigation in order to accurately characterize and treat HS patients.