OMIA:001938-9796 : Congenital liver fibrosis (CLF) in Equus caballus (horse)

Categories: Liver/biliary system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 263200 (trait) , 606702 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: no

Cross-species summary: Cyst formation and fibrotic degeneration of the liver, which ultimately leads to the complete failure of the organ. This phenotype is frequently seen in autosomal recessive polycystic kidney disease (ARPKD) involving cyst formation in the kidney and liver. Congenital liver fibrosis is frequently also called congenital hepatic fibrosis (CHF).

Species-specific name: Congenital liver fibrosis

Species-specific symbol: CLF

Species-specific description: Hepatic fibrosis with cystic bile duct dilatation was observed in two- to twelve-months-old Franches-Montagnes foals. Affected foals commonly show pronounced hepatic encephalopathy with neurological disorders and laboratory findings of hepatic insufficiency. Livers in affected foals become severely enlarged and firm with multiple thin walled cysts. Their weight may be up to four fold higher than normal. Histologically, livers from affected foals show a diffuse portoportal bridging fibrosis with cystic bile ducts, forming a branching network. Affected foals die or are euthanized due to liver insufficiency.

History: Haechler et al. (2000) noted a hereditary liver defect in the Franches-Montagnes horse population. The authors characterized the histopathological lesions in 30 affected foals born between 1984 and 1999. They recognized that this defect is inherited as a monogenic autosomal recessive trait in the Franches-Montagnes horse breed. All affected foals were inbred to a popular stallion born in 1929. Straub et al. (2003) described the clinical symptoms as well as laboratory and pathological findings in seven cases of CLF affected foals. Drögemüller et al. (2014) reported the molecular genetic analysis linking this phenotype to the PKHD1 gene.

Inheritance: CLF is generally considered a monogenic autosomal recessive trait. However, there is considerable variation in the age of onset of the clinical symptoms and disease progression. Together with some unexpected findings during the molecular genetic analysis (Drögemüller et al. 2014), this raises the question whether the inheritance might be slightly more complex involving e.g. incomplete penetrance and possible modifier genes.

Mapping: By conducting a GWAS on 5 cases and 12 controls, each of which had been genotyped with the illumina EquineSNP70 chip (yielding 38,394 informative SNPs), Drögemüller et al. (2014) mapped this defect to chromosome 20. Using a homozygosity analysis they narrowed the critical interval to 952 kb.

Molecular basis: The 952 kb candidate region contains 10 annotated genes. Drögemüller et al. (2014) proposed the PKHD1 gene as plausible functional candidate gene as variants in this gene cause similar phenotypes in other species (human, mouse, rat). The PKHD1 gene encodes a protein, which had also been termed polyductin or fibrocystin (FCYT). In humans most PKHD1 mutations cause cyst formation in the kidney and liver, but a subset of variants cause a liver-restricted phenotype similar to what is seen in CLF affected horses. The PKHD1 gene encodes multiple alternative transcripts, which are not yet fully characterized. By using whole genome sequencing (WGS) and whole transcriptome analysis (RNA-seq) of an affected foal and an obligate carrier Drögemüller et al. identified two nonsynonymous variants in the PKHD1 gene that were strongly, but not perfectly associated with the CLF phenotype (c.6112C>T, p.His2038Tyr and c.6845T>A, p.Ile2282Asn). After genotyping more than 2,300 horses, Drögemüller et al. (2014) identified five non-affected horses that also carried the homozygous variant genotype. On the other hand, one out of 20 investigated CLF affected foals was only heterozygous for these variants. Therefore, Drögemüller et al. (2014) concluded that the molecular basis of CLF cannot be considered fully elucidated. They speculated that the two associated variants might represent pathogenic variants and that the discordant horses might be explained by either the effect of disease-suppressing modifier genes (incomplete penetrance) or in the case of the heterozygous affected foal by haploinsufficiency or a second independent mutation on the other allele.

Clinical features: Affected foals will develop a liver failure, which can result in various clinical findings. Typical findings include fever and neurological symptoms resulting from the decreasing detoxification performance of the failing liver. An ultrasound examination will reveal an enlarged liver with cyst formation and clinical pathology will reveal grossly elevated liver enzymes.

Pathology: The livers of affected foals are enlarged (up to 4-fold) and of a yellow-greyish color. Histologically, diffuse porto-portal bridging fibrosis with many small, irregularly formed and sometimes cystic bile ducts is seen.

Prevalence: The carrier frequency of this recessive defect was estimated at 14% in 2011 (Leeb, unpublished data). Due to the systematic use of an indirect haplotype marker test in the breeding program, the frequency of the deleterious allele is decreasing and affected foals are hardly born any more (as of 2014).

Genetic testing: The University of Bern offers an indirect marker test.

Breeds: Freiberger (Horse) (VBO_0000965), Purebred Spanish (Horse) (VBO_0001056).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
PKHD1 polycystic kidney and hepatic disease 1 (autosomal recessive) Equus caballus 20 NC_009163.3 (50790646..50373816) PKHD1 Homologene, Ensembl , NCBI gene

Cite this entry

Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2024). OMIA:001938-9796: Online Mendelian Inheritance in Animals (OMIA) [dataset].


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.

2024 Durward-Akhurst, S.A., Marlowe, J.L., Schaefer, R.J., Springer, K., Grantham, B., Carey, W.K., Bellone, R.R., Mickelson, J.R., McCue, M.E. :
Predicted genetic burden and frequency of phenotype-associated variants in the horse. Sci Rep 14:8396, 2024. Pubmed reference: 38600096. DOI: 10.1038/s41598-024-57872-8.
2018 Molín, J., Asín, J., Vitoria, A., Sanz, A., Gimeno, M., Romero, A., Sánchez, J., Pinczowski, P., Vázquez, F.J., Rodellar, C., Luján, L. :
Congenital hepatic fibrosis in a purebred Spanish horse foal: Pathology and genetic studies on PKHD1 gene mutations. Vet Pathol 55:457-461, 2018. Pubmed reference: 29402207. DOI: 10.1177/0300985817754122.
2014 Drögemüller, M., Jagannathan, V., Welle, M.M., Graubner, C., Straub, R., Gerber, V., Burger, D., Signer-Hasler, H., Poncet, P.A., Klopfenstein, S., von Niederhäusern, R., Tetens, J., Thaller, G., Rieder, S., Drögemüller, C., Leeb, T. :
Congenital hepatic fibrosis in the Franches-Montagnes horse is associated with the polycystic kidney and hepatic disease 1 (PKHD1) gene. PLoS One 9:e110125, 2014. Pubmed reference: 25295861. DOI: 10.1371/journal.pone.0110125.
2003 Straub, R., Herholz, C., Tschudi, P., Gerber, V., von Tscharner, C., Welle, M. :
Intrahepatic bile duct cysts (Caroli's disease) with liver fibrosis in foals. A synopsis of signs and diagnosis of seven cases. (in German) Tierärztl Prax 31 (G):162-165, 2003.
2000 Haechler, S., Van den Ingh, T.S., Rogivue, C., Ehrensperger, F., Welle, M. :
Congenital hepatic fibrosis and cystic bile duct formation in Swiss Freiberger horses. Vet Pathol 37:669-71, 2000. Pubmed reference: 11105960.

Edit History

  • Created by Tosso Leeb on 31 Oct 2014
  • Changed by Tosso Leeb on 31 Oct 2014
  • Changed by Tosso Leeb on 03 Nov 2014
  • Changed by Imke Tammen2 on 04 Jun 2024