A Splice Site Variant in ADAMTS3 Is the Likely Causal Variant for Pulmonary Hypoplasia with Anasarca in Persian/Persian-Cross Sheep.

Simple Summary: Pulmonary hypoplasia with anasarca, or hydrops fetalis, is a fatal inherited disease reported in several species. Affected fetuses are stillborn and present with the buildup of fluid within body cavities and tissues and under-developed lungs and lymph tissues. The enlarged size of the fetus frequently results in difficult or obstructed labor. This is the first report of the disease in three flocks of Persian/Persian-cross sheep in Australia. We describe the pathology of affected fetuses and conducted genetic research that identified and validated a variant in the ADAMTS3 gene as the likely cause for this recessive disease in these sheep. A diagnostic DNA test was developed which allows selective breeding to reduce the risk of affected animals being born. Pulmonary hypoplasia with anasarca, or hydrops fetalis, is characterized by stillbirth, diffuse oedema, and generalized lymph node hypoplasia. The enlarged fetus frequently causes dystocia. The disease has been reported in cattle and sheep as an inherited condition with a recessive mode of inheritance. This is the first report of the disease in Persian/Persian-cross sheep in Australia. Affected fetuses were reported from three flocks, and a total of eleven affected, eleven obligate carrier, and 188 related Persian/Persian-cross animals were available for analysis, as well as unrelated control animals. SNP genotyping revealed a region of homozygosity in affected animals on ovine chromosome six, which contained the functional candidate gene ADAMTS3. Whole genome sequencing of two affected fetuses and one obligate carrier ewe revealed a single nucleotide deletion, ENSOARG00000013204:g.87124344delC, located 3 bp downstream from a donor splice site region in the ADAMTS3 gene. Sanger sequencing of cDNA containing this variant further revealed that it is likely to introduce an early splice site in exon 14, resulting in a loss of 6 amino acids at the junction of exon 14 and intron 14/15. A genotyping assay was developed, and the ENSOARG00000013204:g.87124344delC segregated with disease in 209 animals, allowing for effective identification of carrier animals. [ABSTRACT FROM AUTHOR]