CLUAP1 variants cause non-syndromic retinitis pigmentosa

To report a novel genetic cause of non-syndromic retinitis pigmentosa (RP) due to biallelic variants in the CLUAP1 gene.

Two unrelated simplex cases (P1, P2) with non-syndromic RP were examined. Clinical data included visual acuity, kinetic visual field, optical coherence tomography, fundus autofluorescence, and electroretinography. Genetic testing was done using Whole Exome Sequencing or Whole Genome Sequencing. The effect of a deep intronic variant was validated using patient-derived RNA.

Symptomatic disease onset occurred during childhood for P1 and at age 40 for P2. P1 showed progressive macular atrophy during the fourth decade, while P2 maintained a visual acuity of 0.5 decimals in the best-seeing eye until the seventh decade. Three novel variants in CLUAP1 (NM_015041.3) were identified. P1 was homozygous for the nonsense c.1192 C > T, p.(Arg398Ter), predicted to produce a truncated protein lacking the final 15 amino acids, a region highly conserved across vertebrate orthologs. P2 was compound heterozygous for a nonsense c.465T > A, p.(Tyr155Ter), predicted to be a loss-of-function variant, and the deep intronic variant c.1093-579G > A (M3). RT-PCR analysis of P2-derived mRNA showed that M3 induces aberrant splicing, resulting in inclusion of a pseudoexon harboring a premature termination codon.

We identified CLUAP1 variants as a molecular cause of non-syndromic RP, extending the gene's previously reported association with a syndromic non-ocular phenotype and with Leber congenital amaurosis. These findings expand the known clinical and mutational spectrum linked to CLUAP1 and support its inclusion as a candidate gene in the diagnostic evaluation of autosomal recessive RP.