Genotype–phenotype correlation in children with hereditary spherocytosis

Abstract

Summary Hereditary spherocytosis (HS) is a common inherited haemolytic anaemia attributed to disturbances in five different red cell membrane proteins. We performed a retrospective study of 166 children with HS and describe the clinical phenotype according to the genotype. In 160/166 (97%) children with HS a disease‐causing mutation was identified. Pathogenic variants in ANK1, SPTB, SLC4A1 and SPTA1 were found in 49%, 33%, 13% and 5% of patients. Children with SLC4A1‐HS had the mildest phenotype, showing the highest haemoglobin (P < 0·001), lowest reticulocyte counts (P < 0·001) and lowest unconjugated bilirubin levels (P = 0·006), and none required splenectomy in childhood (P < 0·001). Conversely, children with autosomal recessive SPTA1‐HS had the most severe clinical phenotype, with almost all patients undergoing splenectomy in early childhood. Patients with ANK1 and SPTB variants showed a similar clinical phenotype. Within each gene, variant type or location did not predict disease severity or likelihood of splenectomy. Among patients with a genetic diagnosis, 47 (29%) underwent splenectomy (23 partial; 24 total) while 57 (36%) underwent cholecystectomy. Total splenectomy led to greater improvements in haemoglobin (P = 0·02). Select use of genetic testing (especially in patients without a family history) may help predict clinical phenotype in childhood and guide family counselling.

Genetic and Clinical Characteristics of Patients With Hereditary Spherocytosis in Hubei Province of China

“…We found no significant difference for any indices between patients carrying ANK1 or SPTB variants. Our data were similar to the those reported in a study by Aggarwal et al (2019) and Tole et al (2020) , where they found that the indices in patients with ANK1 variants were similar to the SPTB group. Moreover, Tole et al (2020) found that the variant type or location within each gene did not predict the disease severity.…”

“…Our data were similar to the those reported in a study by Aggarwal et al (2019) and Tole et al (2020) , where they found that the indices in patients with ANK1 variants were similar to the SPTB group. Moreover, Tole et al (2020) found that the variant type or location within each gene did not predict the disease severity. Here, ANK1 death domain variants were associated with lower levels of MCV and MCH compared to other ANK1 domains, but the number of patients was limited.…”

“…Here, the causal variants could be found in 100% of the cases using targeted NGS. In a recent retrospective study of children with HS by Tole et al (2020) , disease-causing variants had been identified in 160/166 (97%) children with HS. WES may help find the phenotype modifying genes ( Aggarwal et al, 2019 ).…”

Hereditary spherocytosis overlooked for 7 years in a pediatric patient with β-thalassemia trait and novel compound heterozygous mutations of SPTA1 gene

“…The αand β-spectrin protein heterodimers self-aggregate in a head-to-head manner to form tetramers that bind to the lipid membrane via ankyrin, protein 4.2, and band 3 [16]. Tole et al [17] showed that children with autosomal recessive SPTA1-HS had the most severe clinical phenotype with almost all patients requiring splenectomy in early childhood. Consistent with their findings, the proband with severe clinical manifestations in this study had the novel compound heterozygous mutations, c.83G > A and c.190G > A of the SPTA1 gene, and these were respectively inherited from an asymptomatic mother and father.…”

A novel SPTB gene mutation in neonatal hereditary spherocytosis: A case report

“…The clinical manifestations of HS include anemia, jaundice and splenomegaly. Most of the neonates with HS present with jaundice at the early stages of the disease, which then progresses into severe anemia (1). For the neonates with HS aged <1 year, the clinical manifestations are usually severe, with the majority of patients showing initial jaundice and subsequent severe anemia.…”