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Tom Buckley, Penny Clouston, Morag Shanks, Jasmina Cehajic Kapetanovic, Robert E MacLaren; Bi-allelic inheritance of dominant and recessive RP1 mutations raises challenges for genetic counselling. Invest. Ophthalmol. Vis. Sci. 2022;63(7):145 – A0325.
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To report on the presence of both dominant and recessive RP1-related retinitis pigmentosa in different members of the same non-consanguineous family.
In this case series, three members of the same family - the daughter, father and mother - were investigated. They underwent clinical assessment by dilated fundus examination and multimodal imaging. Molecular analysis of 111 genes associated with retinitis pigmentosa and retinitis pigmentosa-like phenotypes was undertaken probing the RP1 gene capturing the coding exons and 10 base pairs of the flanking introns of the 111 genes. Putative pathogenic variants were confirmed by Sanger sequencing.
The 38-year-old father was diagnosed with an asymptomatic mild phenotype of rod-cone dystrophy detected by his optometrist, which was subsequently confirmed to be caused by a previously described dominant 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 mild. Clinical phenotyping of his daughter however showed a severe case of early onset cone-rod dystrophy. The mother was 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 novel c.3843dupT truncating variant inherited from her mother, both located in exon 4 of the RP1 gene.
Mutations in exon 4 of RP1 are known to cause differential dominant and recessive disease. The novel c.3843dupT variant is likely to act in an autosomal recessive manner, since the heterozygous mother is clinically unaffected. Its pathogenicity is also supported by the previously reported c.3843delT mutation at the same nucleotide and results in a similarly truncated RP1 protein. The father is mildly 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.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.
Fundus photos, autofluorescence and OCT images captured from the right eyes of the daughter (top), father (middle) and mother (bottom).
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