Long-Read Sequencing Pinpoints F8 Gene Inversion Behind Haemophilia A in a Weimaraner

Researchers have identified the precise molecular defect behind a case of haemophilia A in a Weimaraner dog family, using long-read sequencing to map a large structural rearrangement of the X chromosome. The study, led by Sabrina Pach, Joel Fonseca Nogueira and Bertram Brenig, describes an inversion of roughly 420 kilobases that disrupts the F8 gene, whose loss of function causes this severe bleeding disorder. Haemophilia A arises from partial or complete loss of function of the X-chromosomal F8 gene and has been reported in at least 17 dog breeds.

Despite this breadth, only five distinct molecular causes had been identified in dogs so far. One of these is a large inversion, also known from human patients, first studied in a research colony of Irish Setters at the University of North Carolina at Chapel Hill. Until now, however, the exact locations of the inversion breakpoint junctions in dogs had not been determined.

The new analysis of the affected Weimaraner male revealed that the inversion spans a segment of the X chromosome with breakpoints located in intron 22 of the F8 gene at position 124,003,000 and in the interval between the chloride intracellular channel 2 (CLIC2) and epsilon-trimethyllysine hydroxylase (TMLHE) genes at position 124,432,668, on reference sequence NC_049260.1. The rearrangement is therefore designated NC_049260.1:g.124003000_124432668inv. The authors report that, as in humans, the inversion most likely results from non-allelic homologous recombination between intron 22 and a region approximately 420 kilobases downstream of the F8 gene.

Because the breakpoint junctions are now defined at the DNA sequence level, carriers of the disorder in this dog family can be tested directly, allowing breeders to identify females carrying the mutation and thereby reduce the risk of haemophilia A in male offspring.

Subject of Research: A 420-kb F8 gene inversion causing haemophilia A in a Weimaraner dog, mapped by long-read sequencing

Article Title: A non-allelic homologous recombination-induced inversion in intron 22 of the F8 gene is causative for haemophilia A in a Weimaraner male dog

Article References: Pach, S., Nogueira, J. F., & Brenig, B. (2026). A non-allelic homologous recombination-induced inversion in intron 22 of the F8 gene is causative for haemophilia A in a Weimaraner male dog. PLOS One, 21(10), e0360975. https://doi.org/10.1371/journal.pone.0360975

Image Credits: AI Generated

DOI: 10.1371/journal.pone.0360975

Keywords: haemophilia A, F8 gene, Weimaraner, long-read sequencing, inversion, non-allelic homologous recombination, intron 22, X chromosome, carrier testing, veterinary genetics, CLIC2, TMLHE