A novel essential splice site variant in SPTB in a large hereditary spherocytosis family

We studied a large family with 22 individuals affected with autosomal dominant hereditary spherocytosis (HS).

Genome-wide linkage, whole-genome sequencing (WGS), Sanger sequencing, RT-PCR, and ToPO TA cloning analyses were performed.

We revealed a heterozygous G>A transition in the 14q23 locus, at position +1 of the intron 8 donor splice site of the spectrin beta, erythrocytic (SPTB) gene. This splice variant (SPTB c.1064+1G>A) was confirmed by Sanger sequencing and showed complete co-segregation with HS in the family. Further RT-PCR reactions and sequencing analysis indicated that the variant leads to the exclusion of exon 8 and subsequent frameshift in exon 9 and a premature stop codon in SPTB. Translation of the altered allele would lead to a truncation with a loss of all spectrin repeat domains in SPTB protein.

This variant is novel and has not been found in any databases. We propose that this splice variant explains the spherocytosis phenotype observed in this large family.