Identification of variants in 94 Chinese patients with hereditary spherocytosis by next‐generation sequencing

Abstract

Hereditary spherocytosis (HS) is the most common type of hereditary erythrocyte membrane disease and has varied phenotypic features and genetic patterns. We herein performed a retrospective study of 94 patients with HS and aimed to investigate the genetic variations and genotype–phenotype correlations using targeted next‐generation sequencing. In 79/94 (84%) patients, 83 HS variants including 67 novel variants were identified. Pathogenic variants of SPTB, ANK1, SLC4A1, SPTA1, and EPB42 were found in 32/79(41%), 22/79(28%), 15/79 (19%), 8/79 (9%), and 3/79 (4%) of the patients respectively, revealing that SPTB is the most frequently mutated HS gene in Eastern China. Most SPTB and ANK1 gene variations were nonsense and frameshift variations. Missense variants were the main variant type of SLC4A1, SPTA1, and EPB42 genes. Interestingly, one SPTA1 variant (p. Arg1757Cys) showed an autosomal dominant inheritance pattern and one EPB42 variant (p. Gln377His) was apparent as a hotspot variation. Furthermore, genotype–phenotype analysis was performed among the five mutated gene groups. Besides the finding that patients with the SLC4A1 variant had the highest mean corpuscular hemoglobin levels, no clear correlations between genotype and phenotype were observed.

A single‐center cohort study of patients with hereditary spherocytosis in Central Europe reveals a high frequency of novel disease‐causing genotypes

“…Lower frequencies of causative ANK1 variants were reported in cohorts from Western Europe (27%) 4 and East Asia (29%) 8 . Stop‐gain and frameshift mutations were found in 75% of our patients with ANK1 variants, similar to results from East 3 and South Asia 7 . Interestingly, the intronic variant leading to a frameshift ( ANK1 , c.1405−9G>A) appears common and was described in different ancestries (Table 1 and Supporting Information S1: Table ).…”

“…HS‐causing defects comprise ANK1 (encoding ankyrin‐1), SPTB (encoding β‐spectrin), SPTA1 (encoding α‐spectrin), SLC4A1 (encoding band 3), and EPB42 (encoding protein 4.2) mutations. HS occurs in all ethnic groups, with differences in overall prevalence and genetic subtypes 2,3 …”

“…HS occurs in all ethnic groups, with differences in overall prevalence and genetic subtypes. 2,3 Next-generation sequencing (NGS) has helped elucidate pathogenic variants underlying HS, the complexity of inheritance modes, and genotype-phenotype correlations in different ancestries including Western Europe, 4 North America, 5 South America, 6 South Asia, 7 and East Asia. 3,8 Moreover, better insights into the structures and interactions of key RBC protein complexes were recently provided.…”

“…2,3 Next-generation sequencing (NGS) has helped elucidate pathogenic variants underlying HS, the complexity of inheritance modes, and genotype-phenotype correlations in different ancestries including Western Europe, 4 North America, 5 South America, 6 South Asia, 7 and East Asia. 3,8 Moreover, better insights into the structures and interactions of key RBC protein complexes were recently provided. 9 Here, we report the results of the first Central European singlecenter study including 113 individuals from 35 families (HS patients, n = 69 including 35 index patients and 34 affected family members; unaffected first-degree relatives, n = 44).…”

“…Missense variants were the most prevalent genomic aberrations (60%), corroborating previous findings. 3,4 The patient with the most severe phenotype in our cohort carries a homozygous variant in SLC4A1 (Band3 null Vienna ) and we provide an update on the clinical course since the first publication 13 (Supporting Information S1: Family F19 and Figure S10).…”