Clinical Characteristics of POC1B-Associated Retinopathy and Assignment of Pathogenicity to Novel Deep Intronic and Non-Canonical Splice Site Variants

Abstract

Mutations in POC1B are a rare cause of inherited retinal degeneration. In this study, we present a thorough phenotypic and genotypic characterization of three individuals harboring putatively pathogenic variants in the POC1B gene. All patients displayed a similar, slowly progressive retinopathy (cone dystrophy or cone-rod dystrophy) with normal funduscopy but disrupted outer retinal layers on optical coherence tomography and variable age of onset. Other symptoms were decreased visual acuity and photophobia. Whole genome sequencing revealed a novel homozygous frameshift variant in one patient. Another patient was shown to harbor a novel deep intronic variant in compound heterozygous state with a previously reported canonical splice site variant. The third patient showed a novel nonsense variant and a novel non-canonical splice site variant. We aimed to validate the effect of the deep intronic variant and the non-canonical splice site variant by means of in vitro splice assays. In addition, direct RNA analysis was performed in one patient. Splicing analysis revealed that the non-canonical splice site variant c.561-3T>C leads to exon skipping while the novel deep intronic variant c.1033-327T>A causes pseudoexon activation. Our data expand the genetic landscape of POC1B mutations and confirm the benefit of genome sequencing in combination with downstream functional validation using minigene assays for the analysis of putative splice variants. In addition, we provide clinical multimodal phenotyping of the affected individuals.

Liver Failure of Wilson's Disease With Manifestations Similar to Porphyria and Uncommon ATP7B Gene Mutation: A Case Report and Literature Review

“…It has been confirmed previously that splice variants can alter the order of intron removal, thereby leading to exon skipping ( 23 ). One study had found that a splice mutation (c.561-3T>C) of intron 6, in the POC1B gene, in which exon 6 is partly skipped ( 24 ). Based on the findings reported in the literature ( 25 ) and those of our case, mRNA sequencing analysis revealed that deep intron deletion on both sides of the affected exon can cause exon jumping, intron retention, or sequence insertion of other genes in mRNA, and intron deletion may be a pathogenic mutation.…”

Functional Analysis of a Novel, Non-Canonical RPGR Splice Variant Causing X-Linked Retinitis Pigmentosa

“…In addition, several recent studies indicate the impact of the NCSS in molecular diagnostics for patients affected by retinal-inherited diseases. Pathogenic NCSSs have been described in many genes associated with inherited retinal dystrophies, including ABCA4 , BEST1 , POC1B , CACNA2D4 , FSCN2 , MAK , MERTK , PRCD , RIMS1 , RP2 , RPGR , or USH2A [ 44 , 46 , 47 , 48 , 49 , 50 ]. Moreover, a large study focusing on ABCA4 has shown that sequencing the entire locus (including the intronic regions) allowed the identification of a molecular diagnosis in 42.5% of the probands with suspected ABCA4 -related retinopathy [ 51 ].…”

A spotter’s guide to SNPtic exons: The common splice variants underlying some SNP–phenotype correlations

“…We predict an associated phenotype equivalent to very mild NF1, which may be detected as elevated cancer risk and elevated risk of neurocognitive impairment. This CE in Proteome Of Centriole Protein 1B (POC1B-OMIM #614784) was detected in blood RNA from a compound heterozygous patient with adult-onset symptoms of reduced visual acuity, reduced visual contrast and photophobia (Weisschuh et al, 2021). Pathogenic mutations to POC1B generally cause some form of retinopathy, although symptoms and age of onset are highly variable.…”