Whole‐exome sequencing uncovered genetic diagnosis of severe inherited haemolytic anaemia: Correlation with clinical phenotypes

Summary Next‐generation sequencing has shed light on the diagnosis of previously unsolved cases of inherited haemolytic anaemia (IHA). We employed whole‐exome sequencing to explore the molecular diagnostic spectrum of 21 unrelated Thai paediatric patients with non‐thalassemic IHA, presenting hydrops fetalis and/or becoming transfusion‐dependent for 1 year or more or throughout their lifespan. Anaemia was detected prenatally, within the first month and the fifth year of life in three, 12 and six patients respectively. Molecular diagnosis obtained from all patients revealed SPTB as the most frequently mutated gene (four reported, three novel), found in 31 of 42 studied alleles. The other two mutated genes identified were ANK1 (three novel) and KLF1 (two reported). Four recurring mutations within exon 29/30 (NM_001024858.2) accounted for the vast majority (90%) of mutated SPTB alleles, biallelic inheritance of which resulted in the most severe phenotypes: hydrops fetalis and life‐long transfusion dependency. Dominant ANK1 ( n = 3) and SPTB ( n = 2) mutations and biallelic class 2 KLF1 mutations ( n = 1) led to a shorter period of transfusion dependency. Our study demonstrated that mutated SPTB causing red‐cell membranopathy is likely the most common cause of severe non‐thalassemic IHA among Thai patients. This urges carrier screening in the population to prevent subsequent, severely affected births.