OMIA:001952-9940 : Microtia in Ovis aries (sheep)

In other species: pig

Categories: Hearing / vestibular / ear phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 600674 (trait) , 142992 (gene) , 612109 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2020

Species-specific description: Hereditary underdevelopment of the ear

Mapping: Having genotyped 8 affected and 12 non-affected sheep each with the Illumina OvineSNP50® chip, Jawasreh et al. (2016) reported that "a single-locus analysis revealed a statistically significant association (P = 0.012, genome-wide) with a SNP at basepair 34 647 499 on OAR23. This marker is adjacent to the gene encoding transcription factor GATA-6, which has been shown to play a role in many developmental processes, including chondrogenesis. The lack of extended homozygosity in this region suggests a fairly ancient mutation, and the time of occurrence was estimated to be approximately 3000 years ago." Mastrangelo et al. (2018) obtained a strong signal on a different chromosome in the Valle del Belice breed: "A total of 40 individuals, 20 with microtia and 20 normal, were genotyped with the Illumina OvineSNP50 BeadChip. The comparison among the results from a genome-wide association study, Fisher's exact test and FST analysis revealed a single strong association signal: rs419889303 on chromosome 1, located within intron 3 of the CLRN1 gene. Our study suggests for the first time that this novel candidate gene is responsible for microtia in sheep." In the Altay breed, a GWAS by He et al. (2020) identified a region on chromosome OAR6. Klawatsch et al. (2023): "we performed genome-wide SNP genotyping and haplotype-based mapping, in a population of 340 individuals, to identify loci influencing ear length variation in ... sheep breeds from Slovenia, Croatia, Cyprus and Greece. Additionally, two previously described candidate variants were also genotyped ... . The mapping model without candidate variant genotypes revealed only one genome-wide significant signal, which was located next to HMX1 on OAR6. This region was previously described as being associated with ear length variation in the Altay and Awassi sheep breeds. The mapping model including the candidate duplication genotype near HMX1 as a fixed effect explained the phenotypic variance on OAR6 and revealed an additional genome-wide significant locus on OAR13 associated with ear length. Our results, combined with published evidence, suggest that a duplication in the evolutionarily conserved region near HMX1 is the major regulator of ear length in sheep breeds descended from a larger region from Central Asia, to the Middle East, Cyprus, Greece and to the Alps. This distribution suggests an ancient origin of the derived allele."

Molecular basis: Within the candidate region on chromosome OAR6, He et al. (2020) identified a 76-bp duplication in the HMX1 gene that was completely concordant with microtia in their sample of 129 Altay sheep, and is absent from 6 other breeds investigated.
Zhang et al. (2024) identified the same 76-bp duplication in Kazakh sheep with microtia and provided additioanl evidence for causality: "...luciferase assays confirmed that this duplication increased HMX1 gene expression, and duplication knock-in mice also exhibited shorter and narrower external ears compared to wild-type mice. Transcriptomic analysis further demonstrated that this duplication enhanced HMX1 gene expression in animal models."

Breeds: Altay Fat-Rumped, China (Sheep) (VBO_0015734), Awassi (Sheep) (VBO_0001308), Kazakh Fat-Rumped (Sheep) (VBO_0001466).
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
HMX1 H6 family homeobox 1 Ovis aries 6 NC_056059.1 (115750422..115745800) HMX1 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
1153 Altay Fat-Rumped, China (Sheep) Awassi (Sheep) Kazakh Fat-Rumped (Sheep) Microtia HMX1 duplication Naturally occurring variant Oar_v4.0 6 g.114173249_114173324dup He et al. (2020) identified a 76 bp duplication in an evolutionary conserved region downstream of HMX1 (duplication of 76bp segment 6:126893417-126893492) in Altay sheep, the variant was later identified in other breeds and validated (PMID:32481741; PMID:38395239). 2020 31691317

Cite this entry

Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2024). OMIA:001952-9940: 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 Klawatsch, J., Papachristou, D., Koutsouli, P., Upadhyay, M., Seichter, D., Russ, I., Mioč, B., Simčič, M., Bizelis, I., Medugorac, I. :
Genetic basis of ear length in sheep breeds sampled across the region from the Middle East to the Alps. Anim Genet 55:123-133, 2024. Pubmed reference: 38069488. DOI: 10.1111/age.13387.
Zhang, L., Liang, L., Kasimu, H., Li, W., Liu, M., Li, H., He, S. :
A 76-base pair duplication within the enhancer region of the HMX1 gene causes sheep microtia. Gene 909:S0378-1119(24)00188-4:148307, 2024. Pubmed reference: 38395239. DOI: 10.1016/j.gene.2024.148307.
2020 He, S., Zhang, Z., Sun, Y., Ren, T., Li, W., Zhou, X., Michal, J.J., Jiang, Z., Liu, M. :
Genome-wide association study shows that microtia in Altay sheep is caused by a 76 bp duplication of HMX1. Anim Genet 51:132-136, 2020. Pubmed reference: 31691317. DOI: 10.1111/age.12876.
Jawasreh, K.I.Z., Al-Omari, H.D. :
Duplication in ECR near HMX1 and a SNP in GATA6 genes regulate microtia in Awassi sheep. Genes (Basel) 11:597, 2020. Pubmed reference: 32481741. DOI: 10.3390/genes11060597.
2018 Mastrangelo, S., Sottile, G., Sutera, A.M., Di Gerlando, R., Tolone, M., Moscarelli, A., Sardina, M.T., Portolano, B. :
Genome-wide association study reveals the locus responsible for microtia in Valle del Belice sheep breed. Anim Genet 49:636-640, 2018. Pubmed reference: 30160299. DOI: 10.1111/age.12719.
2016 Jawasreh, K., Boettcher, P.J., Stella, A. :
Genome-wide association scan suggests basis for microtia in Awassi sheep. Anim Genet 47:504-6, 2016. Pubmed reference: 26990958. DOI: 10.1111/age.12431.
2002 Porter, V. :
Mason's World Dictionary of Livestock Breeds, Types and Varieties. 5th edn. C.A.B International, Wallingford, UK. , 2002.
1930 Lush, J.L. :
Earlessness in Karakul sheep Journal of Heredity 21:107-112, 1930.

Edit History

  • Created by Frank Nicholas on 26 Mar 2016
  • Changed by Frank Nicholas on 03 Sep 2018
  • Changed by Frank Nicholas on 31 Jan 2020
  • Changed by Imke Tammen2 on 14 Dec 2023
  • Changed by Imke Tammen2 on 28 Feb 2024