Compound dominant-null heterozygosity in a family with RP1-related retinal dystrophy

To report on the presence of autosomal dominant and compound dominant-null RP1-related retinitis pigmentosa in the same non-consanguineous family.

The father was minimally symptomatic and referred by his optometrist aged 38. He was diagnosed with rod-cone dystrophy, confirmed to be caused by the previously reported RP1 c.2613dupA mutation. He was reassured that his 11-year-old daughter had a 50% chance of inheriting the same mutation and that the condition, if she had it, would most likely be similar. Clinical phenotyping of his daughter however revealed an early onset cone-rod dystrophy. The mother was entirely asymptomatic and clinically normal. Sanger sequencing of the RP1 gene in the daughter confirmed the presence of biallelic mutations - the dominant c.2613dupA variant from her father and a c.3843dupT truncating variant inherited from her mother, both located in exon 4 of the RP1 gene. The maternal c.3843dupT has previously been reported.

Pathogenic variants in exon 4 of RP1 are known to cause differential dominant and recessive disease. The presence of both phenotypes in a single family has not yet been reported. The father, being minimally symptomatic, is affected by a known dominant variant which truncates the RP1 protein more proximally. However, inheritance of both variants in a compound heterozygous state in the daughter resulted in a much more severe, early onset cone-rod phenotype in a pattern akin to recessive disease. This raises challenges for genetic counselling and development of gene-based therapies for RP1 mutations.