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Feline precision medicine using whole-exome sequencing identifies a novel frameshift mutation for vitamin D-dependent rickets type 2.
Habacher, Gabriele; Malik, Richard; Lait, Philippa Jp; Coghill, Lyndon M; Middleton, Rondo P; Warren, Wesley C; Lyons, Leslie A.
Afiliação
  • Habacher G; Raddenstiles Veterinary Surgery, CVS UK Ltd, Exmouth, UK.
  • Malik R; Centre for Veterinary Education, The University of Sydney, Sydney, NSW, Australia.
  • Lait PJ; Langford Vets, University of Bristol, Langford, Bristol, UK.
  • Coghill LM; Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA.
  • Middleton RP; Nestlé Purina Research, St Louis, MO, USA.
  • Warren WC; Division of Animal Sciences, College of Agriculture, Department of Surgery, School of Medicine, Institute for Data Science and Informatics, University of Missouri, Columbia, MO, USA.
  • Lyons LA; Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA.
J Feline Med Surg ; 25(6): 1098612X231165630, 2023 06.
Article em En | MEDLINE | ID: mdl-37387221
ABSTRACT

OBJECTIVES:

A 14-week-old female domestic longhair kitten presented with shifting lameness and disproportionately smaller size compared with a co-housed littermate.

METHODS:

Hematology and serum biochemical testing were conducted to investigate causes for delayed growth, and radiographs of the appendicular skeleton were obtained.

RESULTS:

The afflicted kitten had marked hypocalcemia, mild hypophosphatemia and substantial elevations in alkaline phosphatase activity, as well as pathognomonic radiographic findings consistent with rickets. Skeletal changes and hypocalcemia prompted testing of concentrations of parathyroid hormone (PTH) and vitamin D metabolites. Endocrine testing demonstrated significant increases in serum concentrations of PTH and 1,25-dihydroxycholecalciferol (calcitriol), supporting a diagnosis of vitamin D-dependent rickets type 2. Provision of analgesia, supraphysiologic doses of calcitriol and calcium carbonate supplementation achieved normalization of the serum calcium concentration and restoration of normal growth, although some skeletal abnormalities persisted. Once skeletally mature, ongoing calcitriol supplementation was not required. Whole-exome sequencing (WES) was conducted to identify the underlying DNA variant. A cytosine deletion at cat chromosome position B476777621 in VDR (ENSFCAT00000029466c.106delC) was identified and predicted to cause a stop codon in exon 2 (p.Arg36Glufs*18), disrupting >90% of the receptor. The variant was unique and homozygous in this patient and absent in the sibling and approximately 400 other cats for which whole-genome and whole-exome data were available. CONCLUSIONS AND RELEVANCE A unique, heritable form of rickets was diagnosed in a domestic longhair cat. WES identified a novel frameshift mutation affecting the gene coding for the vitamin D3 receptor, determining the likely causal genetic variant. Precision medicine techniques, including whole-exome and whole-genome sequencing, can be a standard of care in cats to identify disease etiologies, and to target therapeutics and personalize treatment.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Raquitismo / Doenças do Gato / Hipocalcemia Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Animals Idioma: En Revista: J Feline Med Surg Assunto da revista: MEDICINA VETERINARIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Raquitismo / Doenças do Gato / Hipocalcemia Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Animals Idioma: En Revista: J Feline Med Surg Assunto da revista: MEDICINA VETERINARIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Reino Unido