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

Abstract

Despite the contribution of a few major genes for disproportionate dwarfism in humans, many dwarf patients are yet genetically undiagnosed. In domestic cats, disproportionate dwarfism has led to the development of a defined breed, the Munchkin or Minuet. This study examined the genetic aspects of feline dwarfism to consider cats as a new biomedical model. DNA from dwarf cats was genetically analyzed using parentage, linkage, and genome-wide association studies as well as whole genome sequencing.Each genetic approach localized the dwarfism phenotype to a region on cat chromosome B1. No coding variants suspected as causal for the feline dwarfism were identified but a critical region of ~5.7 Mb from B1:170,278,183-175,975,857 was defined, which implicates a novel gene controlling disproportionate dwarfism. A yet unidentified but novel gene variant, likely structural or regulatory, produces disproportionate dwarfism in cats, which may define undiagnosed human patients.

A new domestic cat genome assembly based on long sequence reads empowers feline genomic medicine and identifies a novel gene for dwarfism

“…[32]. Similar to analyses with cat assemblies Felis_catus-6.2 and Felis_catus_8.0, previous investigations for SNVs in the new Felis_catus_9.0 assembly did not identify any high priority candidate variants for disproportionate dwarfism[27]. However, SV analysis within the critical region previously identified by linkage and…”

“…Dwarfism in cats is the defining feature of the Munchkin breed and is characterized by shortened limbs and normal sized torso ( Fig 4A ) [ 32 ]. Similar to analyses with cat assemblies Felis_catus-6.2 and Felis_catus_8.0, previous investigations for SNVs in the new Felis_catus_9.0 assembly did not identify any high priority candidate variants for disproportionate dwarfism [ 27 ]. However, SV analysis within the critical region previously identified by linkage and GWAS on chromosome B1:170,786,914–175,975,857 [ 27 ] revealed a 3.3 kb deletion at position chrB1:174,882,897–174,886,198, overlapping the final exon of UDP-glucose 6-dehydrogenase (UGDH) ( Fig 4B ).…”

“…Similar to analyses with cat assemblies Felis_catus-6.2 and Felis_catus_8.0, previous investigations for SNVs in the new Felis_catus_9.0 assembly did not identify any high priority candidate variants for disproportionate dwarfism [ 27 ]. However, SV analysis within the critical region previously identified by linkage and GWAS on chromosome B1:170,786,914–175,975,857 [ 27 ] revealed a 3.3 kb deletion at position chrB1:174,882,897–174,886,198, overlapping the final exon of UDP-glucose 6-dehydrogenase (UGDH) ( Fig 4B ). Upon manual inspection of this SV, a 49 bp segment from exon 8 appeared to be duplicated and inserted 3.5 kb downstream, replacing the deleted sequence.…”

“…Breed cats with higher levels of variation and heterozygosity were either from newly established breeds or were outcrossed individuals. For example, Napoleon cats, which all had an F statistic at least one standard deviation below the mean ( Fig 1C and S5 Data ), are frequently outcrossed as their defining trait dwarfism is likely homozygous lethal in utero [ 27 ].…”

Clinical, metabolic, and genetic characterization of hereditary methemoglobinemia caused by cytochrome b5reductase deficiency in cats

“…For Cat 2, a 350 bp library was constructed and sequenced using an Illumina HiSeq X Ten instrument (San Diego, California), both using 150 bp paired‐end reads and producing ~30× coverage. Sequence data were processed and variants filtered using VarSeq software (Golden Helix, Inc, Bozeman, Montana) as previously described . Each cat was investigated separately and assumed as homozygous for DNA variants that would have a major impact on the protein and would be rare (<2%) to absent in the 99 Lives Cat Genome Sequence data set .…”