OMIA:000001-9913 : Haplotype with homozygous deficiency HH1, APAF1-related in Bos taurus (taurine cattle)

In other species: indicine cattle (zebu)

Categories: Mortality / aging (incl. embryonic lethal)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 602233 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive lethal

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2012

Species-specific name: Haplotype HH1

Species-specific symbol: HH1

History: Using genotype data from tens of thousands of North American Holsteins, Jerseys and Brown Swiss cattle each genotyped with approximately 50K SNPs on the BovineSNP50 BeadChip, VanRaden et al. (2011) identified five new recessive lethal haplotypes by searching for common haplotypes that are never homozygous in live animals. Three of these haplotypes occur in Holsteins only, and (following a convention proposed by breed-association staff) VanRaden et al. (2011) named them HH1, HH2 and HH3, where the first H stands for Holstein and the second H for haplotype. The disorder described in this OMIA entry is HH1, which maps to chromosome BTA5, at 58-66Mb (UMD 3.0 genome assembly). Fritz et al. (2013) confirmed the existence and location of HH1.

Molecular basis: Adams et al. (2012) revealed the causal mutation of HH1 as "a nonsense mutation in APAF1 . . . , which is predicted to truncate approximately one-third of the encoded APAF1 protein". Because functional APAF1 peptide is required for embryo development, homozygosity for this allele results in natural spontaneous abortion, and, consequently, perceived reduced fertility in carrier bulls that happen to be mated to carrier cows. Adams et al. (2016) published the causal mutation as being "a nonsense mutation in APAF1 (apoptotic protease activating factor 1; APAF1 p.Q579X) within HH1 using whole-genome resequencing of Chief and 3 of his sons. This mutation is predicted to truncate 670 AA (53.7%) of the encoded APAF1 protein that contains a WD40 domain critical to protein–protein interactions."

Clinical features: Park et al. (2023) report a Holstein foetus with schistosomus reflexus that tested homozygous for the APAF1 variant identified by Adams et al. (2012) (OMIAvariantID:286).

Prevalence: Adams et al. (2016) :"Subsequent commercial genotyping of 246,773 Holsteins revealed 5,299 APAF1 heterozygotes and zero homozygotes for the mutation. . . . This mutation has caused an estimated 525,000 spontaneous abortions worldwide over the past 35 years, accounting for approximately $420 million in losses."

Breeds: Blanco Orejinegro, Colombia (Cattle) (VBO_0004602), Holstein (black and white) (Cattle) (VBO_0000237).
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
APAF1 apoptotic peptidase activating factor 1 Bos taurus 5 NC_037332.1 (62782018..62871543) APAF1 Homologene, Ensembl , NCBI gene


By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.

OMIA Variant ID Breed(s) Variant Phenotype Gene Allele Type of Variant Source of Genetic Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
286 Blanco Orejinegro, Colombia (Cattle) Holstein (black and white) (Cattle) Abortion due to a nonsense mutation in APAF1 on haplotype HH1 APAF1 nonsense (stop-gain) Naturally occurring variant ARS-UCD1.2 5 g.62810245C>T c.1741C>T p.(Q581*) Variant initially reported in Holstein Friesian cattle and later reported in additional breeds: PMID:34779908. rs448942533 2016 27289157 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool; Breed information kindly provided or confirmed by Matt McClure and Jennifer McClure from "Understanding Genetics and Complete Genetic Disease and Trait Definition (Expanded 2016 Edition)" (

Cite this entry

Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2023). OMIA:000001-9913: 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 Khan, M.Y.A., Dai, D., Su, X., Tian, J., Zhou, J., Ma, L., Wang, Y., Wen, W., Zhang, Y. :
Multiplex fluorescent amplification-refractory mutation system PCR method for the detection of 10 genetic defects in Holstein cattle and its comparison with the KASP genotyping assay. Anim Genet , 2024. Pubmed reference: 38622758. DOI: 10.1111/age.13432.
Shormanova, M., Makhmutov, A., Shormanova, A., Muslimova, Z., Ussenbekov, Y. :
Development of alternative diagnosis of HH1, HH3, HH5 and HCD fertility haplotypes and subfertility syndrome in cattle. Reprod Domest Anim 59:e14533, 2024. Pubmed reference: 38268216. DOI: 10.1111/rda.14533.
2023 Ask-Gullstrand, P., Strandberg, E., Båge, R., Rius-Vilarrasa, E., Berglund, B. :
The effect of genetic defects on pregnancy loss in Swedish dairy cattle. J Dairy Sci , 2023. Pubmed reference: 37977438. DOI: 10.3168/jds.2023-24159.
Bengtsson, C., Stålhammar, H., Thomasen, J.R., Fikse, W.F., Strandberg, E., Eriksson, S. :
Mating allocations in Holstein combining genomic information and linear programming optimization at the herd level. J Dairy Sci , 2023. Pubmed reference: 37028963. DOI: 10.3168/jds.2022-22926.
Park, W., Chai, H.H., Lim, D., Dang, C., Lee, J., Kim, J., Jeong, H., Lee, T., Lee, K.C., Lee, K. :
Case report: Investigation of genetic mutations in a case of schistosomus reflexus in a Holstein dairy cattle fetus in Korea. Front Vet Sci 10:1238544, 2023. Pubmed reference: 37671278. DOI: 10.3389/fvets.2023.1238544.
Sudhakar, A., Nayee, N., Saha, S., Donthula, S.K., Poojara, H.V., Gohil, T., Patel, A.C., Maurya, B.K. :
Role of genetic introgression in introducing mutant alleles in Bos indicus cattle and prevalence of lethal genetic disorders in Bos taurus × Bos indicus and Bos indicus cattle in India. Trop Anim Health Prod 55:399, 2023. Pubmed reference: 37940810. DOI: 10.1007/s11250-023-03798-8.
2022 Albertino, L.G., Albuquerque, A.L.H., Ferreira, J.F., Oliveira, J.P.M., Borges, A.S., Patelli, T.H.C., Oliveira-Filho, J.P. :
Allele frequency of APAF1 mutation in Holstein cattle in Brazil. Front Vet Sci 9:822224, 2022. Pubmed reference: 35280144. DOI: 10.3389/fvets.2022.822224.
2021 Caivio-Nasner, S., López-Herrera, A., González-Herrera, L.G., Rincón, J.C. :
Frequency of genotypic markers for genetic disorders, colour, polledness, and major genes in Blanco Orejinegro cattle. Trop Anim Health Prod 53:546, 2021. Pubmed reference: 34779908. DOI: 10.1007/s11250-021-02990-y.
2020 Kamiński, S. :
Novel method for identification of the lethal mutation in bovine APAF1 gene and its preliminary prevalence in Polish Holstein-Friesian bulls. Pol J Vet Sci 23:157-160, 2020. Pubmed reference: 32233301. DOI: 10.24425/pjvs.2020.132760.
2018 Ghanem, M.E., Nishibori, M., Isobe, N., Hisaeda, K. :
Detection of APAF1 mutation in Holstein cows and mummified foetuses in Japanese dairy herds. Reprod Domest Anim 53:137-142, 2018. Pubmed reference: 29076565. DOI: 10.1111/rda.13081.
2016 Adams, H.A., Sonstegard, T.S., VanRaden, P.M., Null, D.J., Van Tassell, C.P., Larkin, D.M., Lewin, H.A. :
Identification of a nonsense mutation in APAF1 that is likely causal for a decrease in reproductive efficiency in Holstein dairy cattle. J Dairy Sci 99:6693-701, 2016. Pubmed reference: 27289157. DOI: 10.3168/jds.2015-10517.
2013 Fritz, S., Capitan, A., Djari, A., Rodriguez, S.C., Barbat, A., Baur, A., Grohs, C., Weiss, B., Boussaha, M., Esquerré, D., Klopp, C., Rocha, D., Boichard, D. :
Detection of haplotypes associated with prenatal death in dairy cattle and identification of deleterious mutations in GART, SHBG and SLC37A2. PLoS One 8:e65550, 2013. Pubmed reference: 23762392. DOI: 10.1371/journal.pone.0065550.
2012 Adams, H.A., Sonstegard, T., VanRaden, P.M., Null, D.J., Van Tassell, C., Lewin, H. :
Identification of a nonsense mutation in APAF1 that is causal for a decrease in reproductive efficiency in dairy cattle. Plant & Animal Genome (PAG) XX :Abstract P0555, 2012.
2011 VanRaden, P.M., Olson, K.M., Null, D.J., Hutchison, J.L. :
Harmful recessive effects on fertility detected by absence of homozygous haplotypes. J Dairy Sci 94:6153-61, 2011. Pubmed reference: 22118103. DOI: 10.3168/jds.2011-4624.
1971 Wijeratne, WVS, Stewart, DL :
Population study of abortion in cattle with special reference to genetic factors Animal Production 13:229-235, 1971.
1963 Mylrea, P.J. :
A suspected genetic cause of abortion in cattle Australian Veterinary Journal 39:35-36, 1963.

Edit History

  • Created by Frank Nicholas on 06 Sep 2005
  • Changed by Frank Nicholas on 03 Oct 2011
  • Changed by Frank Nicholas on 19 Jan 2012
  • Changed by Frank Nicholas on 12 Jun 2013
  • Changed by Frank Nicholas on 14 Jun 2013
  • Changed by Frank Nicholas on 24 Mar 2015
  • Changed by Frank Nicholas on 10 Jun 2016
  • Changed by Frank Nicholas on 14 Jun 2016
  • Changed by Imke Tammen2 on 20 Jan 2023
  • Changed by Imke Tammen2 on 19 Jun 2023
  • Changed by Imke Tammen2 on 07 Sep 2023
  • Changed by Imke Tammen2 on 09 Sep 2023