Multigene Panel Testing Revealed Novel Variants in Hereditary Spherocytosis Patients in Türkiye.

Objective: This study aims to determine the genotypic characteristics of Hereditary Spherocytosis (HS) patients in Turkiye and to examine the correlation between genotype and phenotype.

Materials and methods: Herein we had 18 patients who were admitted to pediatric hematology outpatient clinic with hemolytic anemia, jaundice, cholelithiasis, and splenomegaly. According to the Eber's classification, the patients' clinical presentations were categorized as mild, moderate, and severe. The next-generation sequencing method was used to analyze single nucleotide and copy number variations in all genes associated with HS via clinical exome sequencing (CES). The relationship between the genes with detected variants and the clinical presentation in the patients was investigated.

Results: In total, 21 variants were detected in five HS-related genes. Twelve of them were previously reported variants, and nine of them were novel variants. Seven of them were pathogenic and two of them were classified as Variant of Uncertain Significance (VUS) according to the American College of Medical Genetics and Genomics (ACMG). Herein we have discussed the phenotypic effects of novel pathogenic variants in SPTA1, SPTB, ANK1, SLC4A1, and EPB42 genes. Patients with EPB42 and SLC4A1 gene pathogenic variants had less severe clinical findings compared to other gene variants according to Eber's classification. On the other hand, patients carrying pathogenic variants of SPTA1 and SPTB genes had more severe clinical presentation.

Conclusion: Molecular diagnosis of HS is important for treatment, prediction of the clinical outcome, and appropriate genetic counseling. As a result, our study contributes to the genotype-phenotype distribution of HS by introducing novel variants to the literature.