Precision Medicine in Cats: Novel Niemann‐Pick Type C1 Diagnosed by Whole‐Genome Sequencing

Abstract

State‐of‐the‐art health care includes genome sequencing of the patient to identify genetic variants that contribute to either the cause of their malady or variants that can be targeted to improve treatment. The goal was to introduce state‐of‐the‐art health care to cats using genomics and a precision medicine approach. To test the feasibility of a precision medicine approach in domestic cats, a single cat that presented to the University of Missouri, Veterinary Health Center with an undiagnosed neurologic disease was whole‐genome sequenced. The DNA variants from the cat were compared to the DNA variant database produced by the 99 Lives Cat Genome Sequencing Consortium. Approximately 25× genomic coverage was produced for the cat. A predicted p.H441P missense mutation was identified in NPC1, the gene causing Niemann‐Pick type C1 on cat chromosome D3.47456793 caused by an adenine‐to‐cytosine transversion, c.1322A>C. The cat was homozygous for the variant. The variant was not identified in any other 73 domestic and 9 wild felids in the sequence database or 190 additionally genotyped cats of various breeds. The successful effort suggested precision medicine is feasible for cats and other undiagnosed cats may benefit from a genomic analysis approach. The 99 Lives DNA variant database was sufficient but would benefit from additional cat sequences. Other cats with the mutation may be identified and could be introduced as a new biomedical model for NPC1. A genetic test could eliminate the disease variant from the population.

Long‐term Treatment with Methylene Blue in a Dog with Hereditary Methemoglobinemia Caused by Cytochrome b5 Reductase Deficiency

“…3 A recent improvement in the instrumentation for massively parallel DNA sequencing has decreased the cost of generating mammalian whole-genome sequences so that it is now a cost-effective tool for diagnosing heritable diseases in veterinary patients. 1,7 Thus, once a diagnosis of inherited methemoglobinemia was suspected, we sequenced the dog's genome and identified 2 heterozygous CYB5R3 missense mutations that may be responsible for the cytochrome b5 reductase deficiency. There is strong indirect evidence for a causal contribution from 1 of them: CYB5R3:p.Gly72Ser.…”

Localization of a feline autosomal dominant dwarfism locus: a novel model of chondrodysplasia

“…Three unrelated dwarf cats were submitted for whole genome sequencing as part of the 99 Lives Cat Genome Sequencing Consortium as previously described [23][24][25][26] (BioProject PRJNA308208, PRJNA288177; BioSamples: SAMN05980349, SAMN05980348, SAMN05980352). Reads were mapped to Felis_catus_9.0 (GCF_000181335.3/) and assigned to read groups using BWA-MEM from Burrows-Wheeler Aligner version 0.7.17 27 .…”

AnAms1.0: A high-quality chromosome-scale assembly of a domestic cat Felis catus of American Shorthair breed

“…In human medicine, this approach has been made possible by the preparation of the high-quality human reference genome as a foundation and the large-scale accumulation and integration of disease-related gene annotation and genetic variation information such as Clinvar (Landrum et al 2013). Recent studies have shown in precision medicine in companion animals (Mauler et al, 2017, Mealey et al, 2019. Here, we have constructed a chromosome-level genome assembly for a breed of cat, and are about to launch an information foundation for pet precision medicine for the future of the veterinary care.…”

“…These studies have also uncovered genetic variations among breeds. More recently, genome-wide analyses using high-throughput sequencers have identified breed-specific genetic variations and several candidate genes or genetic regions associated with diseases or traits (Aberdein et al, 2016;Lyons et al, 2016;Xu et al, 2016;Bertolini et al, 2016;Mauler et al, 2017;Buckley et al, 2020).…”