In other species: rock pigeon , chicken , dog , lesser panda , horse , goat , sheep

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

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 274500 (trait) , 606765 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0010133: thyroid dyshormonogenesis 2A

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2015

Cross-species summary: Deficiency of thyroid gland activity. Also known as Goiterous congenital hypothyroidism; Congenital hypothyroidism; Thyroid dyshormonogenesis. This disorder can be caused by mutations in different genes, and forms of the disease exist that are not inherited.

History: The occurrence of this disorder in a family of Domestic shorthair cats was reported by Mazrier et al. (2003)

Inheritance: In the family reported by Mazrier et al. (2003), autosomal recessive inhetitance was observed.

Molecular basis: By partially sequencing a strong candidate gene Morrow et al. (2006) reported the molecular basis of this disorder in Domestic shorthair cats as being very likely due to an 8bp deletion in intron 9 of the gene for the enzyme thyroid peroxidase (TPO). Further investigation by the same team identified a causal missense mutation in the TPO gene (c.1333G>A; p.Ala445Thr) (Giger et al., 2015). Van Pouke et al. (2022) investigated 11 "CH [congenital hypothyroidism]-cats from 10 unrelated families [and different breeds], 11 CH-free family members, 21 unrelated CH-free cats, and 155 unrelated nondiagnosed cats from different breeds. ... Based on the clinical phenotype of the cases and literature data, TPO was chosen as the strongest candidate gene ... . Cases were first checked to carry the TPO CH-causing variant NC_018725.3 (XM_006930524.4):c.1333G>A(p.(Ala445Thr)) described by Giger et al. [2015]. ... this variant was not observed in any of the cases ... . Sequencing all coding TPO exons revealed 11 SNVs ... the c.430G>A(p.(Gly144Arg)) variant was prioritized and genotyped in all CH family members, 21 unrelated CH-free cats and 155 unrelated nondiagnosed cats ... . All cases were homozygous, all sampled parents were heterozygous, and none of the sampled healthy family members were homozygous for this variant. ... From the 155 unrelated nondiagnosed cats, 129 did not carry the variant, 23 were heterozygous, and 3 were homozygous for the variant ... . The variant was found in 15 breeds, namely the Balinese, Birman, British Longhair, British Shorthair, Chartreux, Domestic Shorthair, Domestic Medium Hair, Domestic Longhair, Exotic Shorthair, Main Coon, Norwegian Forest Cat, Oriental Shorthair, Russian Blue, Siberian, and Sphynx.

Clinical features: The most common clinical feature of a cat with congenital hypothyroidism is disproportionate dwarfism. Some features of this include a large skull with shortened mandible and ears, a square trunk and short neck (with possible goitre) and limbs, delayed eruption of deciduous and permanent teeth, and occasionally kyphosis. It is also characterised by mental deficiency, and abnormalities of the central and peripheral nervous system. Other less specific features include hypothermia, anorexia, obesity, constipation, lethargy, a persistent juvenile hair coat and delayed closure of growth plates (Greco, 2006; Hermans et al., 2020) [IT thanks DVM student Rhyanna Boyce, who provided the basis of this contribution in April 2022]

Pathology: An analysis of the biochemistry and haematology of the blood can show hypercholesterolemia, hypercalcaemia, mild non-regenerative anaemia, and low levels of thyroid hormones (T4 and THS, or thyroid scintigraphy) in a cat with congenital hypothyroidism. As thyroid hormones are key to bone development, epiphysial ossification and epiphysial dysgenesis are common features of congenital hypothyroidism. Spinal radiographs can demonstrate severely shortened vertebral bodies and open growth plates (Greco, 2006; Hermans et al., 2020; Golinelli et al., 2022) [IT thanks DVM student Rhyanna Boyce, who provided the basis of this contribution in April 2022]

Breeds: British Shorthair (Cat) (VBO_0100052), Domestic Longhair, Domestic medium-haired, Domestic Shorthair, Russian Blue (Cat) (VBO_0100200).
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: