Clustering of pathogenic variants in specific regions has also been observed in splicing factor RP genes. For example, pathogenic variants in
PRPF8 and
SNRNP200 were clustered in their interaction regions, where defects disrupted PRPF8–SNRNP200 interactions.
47–49 Previously, situations similar to that of
TOPORS have been reported in the
RP1 gene, in which causative heterozygous truncating variants are only located in a specific region in the middle of the gene.
50–52 Regarding
TOPORS, products resulting from pathogenic truncating variants located in the last exon and downstream of the SR/RS domain may escape nonsense-mediated mRNA decay (NMD)
53 and reduce the activity of the wild-type allele via the dominant-negative effect. The normal function of
TOPORS in photoreceptor cilia requires a complete SR/RS domain,
54 which promotes assembly and activation of the spliceosome by binding to the exonic splicing enhancer.
55–57 Thus, N-terminus truncating variants will likely trigger NMD and eliminate aberrant transcripts, whereas CNVs will lead to a null
TOPORS allele. Protein expression from the wild-type
TOPORS allele may be sufficient to maintain a normal phenotype. Therefore, it is speculated that the dominant-negative effect, rather than haploinsufficiency, is the underlying molecular mechanism; however, further functional studies are needed to confirm this. Recently, Weisschuh et al.
41 detected a C-terminal truncating variant, c.3090dup/p.(Thr1031Aspfs*10), by targeted next-generation sequencing in a cohort of 1785 families with inherited retinal degeneration. However, the allele frequency of this variant was 2/282,804 in the gnomAD database. This variant is located at the C-terminus of
TOPORS, where truncating variants in the gnomAD database appear slightly clustered (
Fig. 1A). Therefore, individuals with variants in the C-terminus should undergo a detailed clinical evaluation and co-segregation analysis.