Whole genome sequencing identifies novel candidate genetic variants in canine stomatocytosis

Wallace, M.D.; Falcone, S.; Castillo, D.; Williams, T.L.; Davison, L.J.

Abstract

Abstract
Stomatocytosis is a rare spectrum of red blood cell (RBC) disorders. In humans, stomatocytosis is typically caused by genetic changes in specific ion exchange and transport genes. Stomatocytosis has been identified in dogs, however the underlying genetic causes are unknown. Recently, stomatocytosis was reported in a Beagle and Australian Cattle Dog for the first time. Here, whole-genome sequencing (WGS) of these dogs was undertaken to identify candidate genetic variants driving or impacting stomatocytosis. Cases were compared to WGS of 119 controls of several breeds and > 1,000 dogs from public and private datasets. Candidate genes were identified, including genes linked to stomatocytosis in humans: SPTB and KCNN4. Notably, each case carried a different homozygous intronic SNP in SPTB only 24 bases apart (Beagle − chr8:39,194,923; ACD − chr8:39,194,947; CanFam3.1), which were not homozygous in other dogs. Variants with predicted deleterious impact in additional ion transport-related genes were also identified: SLC8A3, DYSF, SLC12A8, INPP5E, SLC1A1, and a novel SLC41A3 genetic change carried by the Australian Cattle Dog. Human and mouse scRNAseq and proteomics data indicate that these candidate genes are expressed in RBCs or their immature precursors. Taken together, these genetic data obtained from spontaneous stomatocytosis in a non-human species provide novel insights and candidate genes for evaluation of rare red cell disorders in humans.

Citation

Wallace, M., Falcone, S., Castillo, D., Williams, T., & Davison, L. (2025). Whole genome sequencing identifies novel candidate genetic variants in canine stomatocytosis. Gene, 149314. https://doi.org/10.1016/j.gene.2025.149314

• Journal Article Type: Article
• Acceptance Date: Feb 3, 2025
• Online Publication Date: Feb 12, 2025
• Publication Date: 2025-02
• Deposit Date: Feb 12, 2025
• Publicly Available Date: Feb 26, 2025
• Journal: Gene
• Print ISSN: 0378-1119
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Pages: 149314
• DOI: https://doi.org/10.1016/j.gene.2025.149314
• Additional Information: This article is maintained by: Elsevier; Article Title: Whole genome sequencing identifies novel candidate genetic variants in canine stomatocytosis; Journal Title: Gene; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.gene.2025.149314; Content Type: article; Copyright: © 2025 The Author(s). Published by Elsevier B.V.