A deletion inGDF7is associated with a heritable forebrain commissural malformation concurrent with ventriculomegaly and interhemispheric cysts in cats

Abstract

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, 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 99Lives dataset. The variant segregated concordantly in an extended pedigree. Obligate carrier cats were heterozygous. In mice, GDF7 mRNA is expressed within the roof plate when commissural axons initiate ventrally-directed growth. This finding emphasizes 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.

A domestic cat whole exome sequencing resource for trait discovery

“…Of these known variants, 44 were identified in our WES cohort. All variants for coat colors and diseases expected to be present in the ten cats were identified, including the alleles in the loci for Agouti ( ASI P—a 20 ), Brown ( TYRP1 —b 21 ), Color ( TYR —cs 22 ), Dense ( MLPH —d 23 ), Longhair ( FGF5 —I 24 ), Lykoi ( HR —hrTN, hrVA 25 ), Bengal progressive retinal degeneration ( KIF3B 26 ) and Persian progressive retinal degeneration ( AIPL1 17 ), hydrocephalus ( GDF7 27 ), and others (Supplementary Data S5 ). The cats also had variants known to affect cat blood type as well 28 , 29 .…”

A domestic cat whole exome sequencing resource for trait discovery

“…Forty-four known variants were identified in the WES cohort. All variants for coat colors and diseases known to be present in the ten cats were identified, including the alleles in the loci for Agouti ( ASIP - a 48 ), Brown (TYRP1 – b) 49 , Color (TYR – c s ) 50 , Dense (MLPH) 51 , Longhair ( FGF5 ) 52 , Lykoi ( HR ) 53 , Bengal ( KIF3B ) 54 and Persian progressive retinal degeneration ( AIPL1 ) 27 , hydrocephalus ( GDF7 ) 55 , and others ( Supplementary Data 5) . The cats had various known mutations affecting cat blood type.…”