Association of recessive c.430G>A (p.(Gly144Arg)) thyroid peroxidase variant with primary congenital hypothyroidism in cats

Abstract Background Primary congenital hypothyroidism (CH) is a rare endocrine disorder in cats with a largely unknown genetic cause. Objectives Describe the clinical presentation of CH in 11 affected cats and identify the causal genetic variant. Animals Eleven CH‐cats from 10 unrelated families, 11 CH‐free family members, 21 unrelated CH‐free cats, and 155 unrelated nondiagnosed cats from different breeds. Methods Case control study of CH‐cats and their siblings (2019‐2021). Diagnosis was based on low to low‐normal serum thyroxine (T4) concentrations, high thyroid‐stimulating hormone (TSH) concentrations and clinical signs compatible with CH. We identified the causal variant using Sanger sequencing, genotyping via PCR‐RFLP and variant interpretation using ACMG/AMP guidelines. Results All CH‐cats (5 weeks‐8 years) had disproportionate dwarfism. A goiter was not palpable in all. Thyroid scintigraphy with radiopertechnetate showed abnormally high uptake by thyroid glands, whereas scintigraphy with radioiodine showed abnormally low uptake, compatible with a defect in iodine organification by thyroid peroxidase (TPO). All cases were homozygous for TPO variant XM_006930524.4:c.430G>A(p.(Gly144Arg)), while none of the CH‐free cats were. All sampled parents were heterozygous for this recessive variant. This variant was found in 15 cat breeds with an estimated allele frequency of 9%. Conclusions and Clinical Importance Disproportionate dwarfism, abnormally high TSH and abnormally low to low‐normal T4 concentrations are diagnostic for CH in cats. All cases had dyshormonogenesis demonstrated by thyroid scintigraphy. This novel TPO missense variant (not described in humans) causes CH in cats and awareness of it can assist in diagnosis and breeding.