OMIA 002458-9796 : Hypoparathyroidism, RAPGEF5-related in Equus caballus

Possibly relevant human trait(s) and/or gene(s) (MIM number): 609527 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2020

Inheritance: Rivas et al. (2020) reported evidence consistent with autosomal recessive inheritance.

Molecular basis: Rivas et al. (2020): "We performed whole-genome sequencing of the two foals, their unaffected dams and four unaffected, unrelated TB horses. Both homozygosity mapping and an association analysis were used to prioritize potential genetic variants. Of the 2,808 variants that significantly associated with the phenotype using an AR mode of inheritance (P<0.02) and located within a region of homozygosity, 1,507 (54%) were located in a 9.7 Mb region on chr4 (44.9-54.6 Mb). Within this region, a nonsense variant (RAPGEF5 c.2624C>A,p.Ser875*) was significantly associated with the hypoparathyroid phenotype (Pallelic = 0.008). Affected foals were homozygous for the variant, with two additional affected foals subsequently confirmed in 2019."

Clinical features: Beyer et al. (1997): “Five thoroughbred foals (4 fillies and 1 colt), all in good to excellent body condition, ranging in age from 4 days to 5 weeks at the time of onset of signs, were presented … . All 5 foals presented with tachycardia, hyperhidrosis, diarrhea or a recent history of diarrhea, and muscle rigidity or stiff gait. Four of the 5 foals presented for recumbency, seizure-like activity with opisthotonos, or pronounced extensor muscle rigidity. All 5 foals were hypocalcemic. All foals either died or had euthanasia performed.”

The foals investigated by Rivas et al. (2020) presented with fatal idiopathic hypocalcemia, tetany and seizures.

Pathology: In four of the 5 foals reported by Beyer et al. (1997) necropsy examination were conducted and in all 4 foals parathyroid tissue could not be identified.

In the cases reported by Rivas et al. (2020) the only consistent gross or histologic lesions present across all cases was the absence of normal parathyroid glands.

Breed: Thoroughbred.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
RAPGEF5 Rap guanine nucleotide exchange factor 5 Equus caballus 4 NC_009147.3 (54325254..54104253) RAPGEF5 Homologene, Ensembl, NCBI gene

Variants

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.

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 Inferred EVA rsID Year Published PubMed ID(s) Acknowledgements
Thoroughbred Hypoparathyroidism RAPGEF5 nonsense (stop-gain) Naturally occurring variant EquCab3.0 4 g.54108297G>T c.2624C>A p.(S875*) 2020 32986719

References


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.
2020 Rivas, V.N., Magdesian, K.G., Fagan, S., Slovis, N.M., Luethy, D., Javsicas, L.H., Caserto, B.G., Miller, A.D., Dahlgren, A.R., Peterson, J., Hales, E.N., Peng, S., Watson, K.D., Khokha, M.K., Finno, C.J. :
A nonsense variant in Rap Guanine Nucleotide Exchange Factor 5 (RAPGEF5) is associated with equine familial isolated hypoparathyroidism in Thoroughbred foals. PLoS Genet 16:e1009028, 2020. Pubmed reference: 32986719. DOI: 10.1371/journal.pgen.1009028.
1997 Beyer, M.J., Freestone, J.F., Reimer, J.M., Bernard, W.V., Rueve, E.R. :
Idiopathic hypocalcemia in foals. J Vet Intern Med 11:356-60, 1997. Pubmed reference: 9470161. DOI: 10.1111/j.1939-1676.1997.tb00480.x.

Edit History


  • Created by Imke Tammen2 on 22 Oct 2021
  • Changed by Imke Tammen2 on 22 Oct 2021