Categories: Endocrine / exocrine gland phene (incl mammary gland)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 609527 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: 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.

Prevalence: Elcombe et al. (2022) reported the c.2624C>A variant (OMIA variant 1369) at a frequency of less than 1% in the US Thoroughbred population (1988-2019).

Breed: Thoroughbred (Horse) (VBO_0001083).
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: