Three novel heterozygous ANK1 loss-of-function variants cause hereditary spherocytosis in Chinese families.

Background and purposes: Hereditary spherocytosis (HS) is an inherited hemolytic anemia caused by variants in red blood cell cytoskeleton proteins. Advances in sequencing technology have revealed numerous novel variants; however, accurate genome annotation remains a significant challenge. In precision medicine, the precise identification of variants responsible for genetic diseases is crucial. This study aims to clearly delineate pathogenic variants and provide targeted pathogenicity analyses.

Methods: We analyzed clinical data from three unrelated Chinese families with HS. Our investigation delved into the pathogenicity and underlying mechanisms of these variants. In silico simulations and in vitro experiments were employed to assess the effects of the identified variants.

Results: We identified three novel heterozygous variants in the ANK1 gene: c.558delG (p.R187Afs*66), c.728T > G (p.L243R), and c.3157 C > T (p.R1053X). In silico analysis indicated that these variants adversely affect the ankyrin-1. Functional studies demonstrated that these variants disrupt the synthesis of ankyrin-1, weakening its interaction with other red blood cell cytoskeleton proteins, which may lead to HS due to the loss of ankyrin-1 function.

Conclusions: Our study offers valuable insights into the molecular mechanisms associated with HS linked to three de novo ANK1 variants. These findings deepen our understanding of the pathogenesis of HS and emphasize the critical role of genetic screening in the diagnosis of this condition.