In humans, the prevalence of congenital microphthalmia is estimated to be 0.2 to 3.0 every 10,000 individuals, with non-ocular involvement reported in ~80% of cases. Inherited eye diseases have been widely and descriptively characterized in dogs, and canine models of ocular diseases have played an important role in understanding the pathophysiology and development of new therapies. A naturally occurring canine model of a syndromic disorder characterized by microphthalmia was discovered in the Portuguese Water Dogmodel of a syndromic disorder characterized by microphthalmia in the Portuguese Water Dog (PWD). As non-ocular findings included tooth enamel malformations, stunted growth, anemia, and thrombocytopenia, we hence termed this disorder Canine Congenital Microphthalmos with Hematopoietic Defects (cCMHD). GWAS and homozygosity mapping detected a 2-Mb candidate region on canine chromosome 4. Whole genome sequencing and mapping against the Canfam4 reference revealed a SINE element insertion in exon 2 of the DNAJC1 gene (g.74,274,883ins[T70]TGCTGCTTGGATT). Subsequent Real-Time PCR-based mass genotyping of a larger PWD population found the homozygous mutant genotype perfectly associated with the cCMHD phenotype. Biallelic variants in DNAJC21 are mostly found to be associated with bone marrow failure (BMF) syndrome type 3, with a phenotype that has a certain degree of overlap with Fanconi anemia, dyskeratosis congenita, Shwachman–Diamond syndrome, Diamond–Blackfan anemia, and reports of individuals showing thrombocytopenia, microdontia and microphthalmia. We therefore propose cCMHD as a naturally occurring model for DNAJC21-associated syndromes.

Blood samples were gathered of cases and controls - Portuguese Water Dogs affected and unaffected by syndromic congenital microphthalmia. DNA was extracted with standard methods.

A subset of these was genotyped on 220k illumina canine SNP chip for homozygosity mapping and GWAS.

Whole genome sequencing (Illumina Hiseq2000) of a single case was carried out to explore the candidate region.

SNP chip data are in plink format, easily convertible to vcf through plink 1.9 or plink 2.0. Also readable as-is (or easily processed) by several R packages.

Whole Genome data are in fastq format, which can be mapped to a reference using standard mappers like BWA.