OMIA 000001-9913 : Abortion due to haplotype HH1, APAF1-related in Bos taurus

Possibly relevant human trait(s) and/or gene(s) (MIM number): 602233

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."

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."

Breed: Holstein.

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 (62781941..62871540) 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.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Friesian Holstein Abortion due to a nonsense mutation in APAF1 on haplotype HH1 APAF1 nonsense (stop-gain) UMD3.1 5 g.63150400C>T c.1741C>T p.Q581* 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)" (


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.
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