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Open AccessArticle

A Deletion in GDF7 is Associated with a Heritable Forebrain Commissural Malformation Concurrent with Ventriculomegaly and Interhemispheric Cysts in Cats

1
Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA
2
Laboratory of Veterinary Radiology, Nippon Veterinary and Life Science University, Musashino, Tokyo 180-8602, Japan
*
Author to whom correspondence should be addressed.
The authors contributed equally to this work.
Membership of the 99 Lives Consortium is provided in the Acknowledgments.
Genes 2020, 11(6), 672; https://doi.org/10.3390/genes11060672
Received: 15 May 2020 / Revised: 10 June 2020 / Accepted: 16 June 2020 / Published: 19 June 2020
(This article belongs to the Special Issue Molecular Basis of Inherited Diseases in Companion Animals)
An inherited neurologic syndrome in a family of mixed-breed Oriental cats has been characterized as forebrain commissural malformation, concurrent with ventriculomegaly and interhemispheric cysts. However, the genetic basis for this autosomal recessive syndrome in cats is unknown. Forty-three cats were genotyped on the Illumina Infinium Feline 63K iSelect DNA Array and used for analyses. Genome-wide association studies, including a sib-transmission disequilibrium test and a case-control association analysis, and homozygosity mapping, identified a critical region on cat chromosome A3. Short-read whole genome sequencing was completed for a cat trio segregating with the syndrome. A homozygous 7 bp deletion in growth differentiation factor 7 (GDF7) (c.221_227delGCCGCGC [p.Arg74Profs]) was identified in affected cats, by comparison to the 99 Lives Cat variant dataset, validated using Sanger sequencing and genotyped by fragment analyses. This variant was not identified in 192 unaffected cats in the 99 Lives dataset. The variant segregated concordantly in an extended pedigree. In mice, GDF7 mRNA is expressed within the roof plate when commissural axons initiate ventrally-directed growth. This finding emphasized the importance of GDF7 in the neurodevelopmental process in the mammalian brain. A genetic test can be developed for use by cat breeders to eradicate this variant. View Full-Text
Keywords: feline; Felis catus; brain malformation; BMP12; neurodevelopment; genetics; genomics; mendelian traits; genome-wide association study; whole genome sequencing feline; Felis catus; brain malformation; BMP12; neurodevelopment; genetics; genomics; mendelian traits; genome-wide association study; whole genome sequencing
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    Doi: https://doi.org/10.1101/2020.05.12.091686
    Description: Table S1: Regions of homozygosity was unique to 18 cats with the inherited forebrain commissural malformation, and were absent in all the unaffected cats. Figure S1: Pedigree of cats segregating for an autosomal recessive forebrain commissural malformation. Relationships of 79 cats (27 nuclear families) provided by the breeder and confirmed with genetic testing of short tandem repeats when possible. Arrow indicates the proband. Circles indicate females, squares indicate males, and diamonds indicate unknown sex. Filled symbols represent cats with small rounded ears, which were suspected to have forebrain commissural malformation concurrent with ventriculomegaly and interhemispheric cysts. Half-filled represent obligate carriers. Symbols with question marks represent cats with unknown phenotype. A symbol with no fill indicates the cat is known to be completely unrelated and not expected to be a carrier. The cats genotyped on the DNA array and used for genome-wide association studies and homozygosity mapping are indicated by a “T” on the upper left of the symbol (The nine cats removed by quality control are not indicated). A black filled circle at the left bottom of symbol are individuals that were whole genome sequenced. Cats with a bar above the symbol were confirmed by magnetic resonance imaging. Cats with an open circle to the upper right had histology performed at necropsy. The cats’ ID/name is indicated below the symbol. Size in basepairs of the genotypes for the 7 bp GDF7 indel are indicated below each cat available. Figure S2: Multi-dimensional scaling plot and quantile-quantile plot of cases and controls for genome-association analyses. (a) Multi-dimensional scaling (MDS) plot of cats used for the initial case-control association analysis. The genomic inflation was 1.89. Therefore, cats clustered within the blue rectangular area were selected for the second case-control association analysis as visual inspection suggests less stratification between cases and controls. The genomic inflation factor was reduced to 1. (b, c) The quantile-quantile plots of cats used for the initial (b) and second (c) analyses demonstrate the observed versus expected–log(p) values. Figure S3: Protein sequence alignment of GDF7 in cats (Felis catus) and other species. GDF7 protein sequences are aligned from wildtype cat (Felis catus), GDF7 mutant cat, cow (Bos Taurus: NP_001193030.1 [ARS-UCD1.2]), horse (Equus caballus: XP_023475218.1 [EquCab3.0]), mouse (Mus musculus: NP_001299805.1 [GRCm38.p4]), and rat (Rattus norvegicus: XP_006239940.1 [Rnor_6.0]). Identical amino acids to those of Felis catus sequence are represented as a dot (.). Deleted amino acids are represented as a dash (–). A 7 bp deletion causes a frameshift and changes the amino acid sequence from 74th position (highlighted in yellow), starting with an arginine to a proline change, which results in the truncated protein with a stop codon 17 amino acids downstream. Figure S4. Variant validation by Sanger sequencing and fragment analysis. (a) Sanger sequence of a wildtype and homozygous affected cat for the 7 bp GDF7 variant (boxed region). (b) Fluorescence-based fragment analysis using an ABI 3730XL for the GDF7 variant. Left – homozygous wildtype with 294 bp fragment, middle – heterozygous with 287 and 294 bp fragments, and right – affected with 287 bp fragment. LIZ standard (Applied Biosystems, Foster City, CA, USA) was used to size DNA fragments. File S1: Ped file for PLINK of cats genotyped using Illumina Infinium Feline 63K iSelect DNA Array. File S2: SNPs (n = 81) forming common haplotype for cats in the association studies.
MDPI and ACS Style

Yu, Y.; Creighton, E.K.; Buckley, R.M.; Lyons, L.A.; 99 Lives Consortium. A Deletion in GDF7 is Associated with a Heritable Forebrain Commissural Malformation Concurrent with Ventriculomegaly and Interhemispheric Cysts in Cats. Genes 2020, 11, 672.

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