Reporting a Homozygous Case of Neurodevelopmental Disorder Associated With a Novel PRPF8 Variant

Abstract

Background: While recently identified heterozygous PRPF8 variants have been linked to various human diseases, their role in neurodevelopmental disorders (NDDs) remains ambiguous. This study investigates the potential association between homozygous PRPF8 variants and NDDs. Most PRPF8 variants are primarily associated with retinal diseases; however, we analyze a family with multiple members diagnosed with NDDs.

Methods: Using exome sequencing (ES), the cause of behavioral problems and intellectual disabilities (IDs) of two sisters from a consanguineous parents was solved, and the results confirmed by direct sanger sequencing method likewise protein modeling to assess the structural impact of the identified variant on the PRPF8 protein has been done.

Results: ES identified a novel homozygous variant, PRPF8 c.257G>T, p.R86M. To the best of our knowledge at the time of writing this manuscript, the mentioned variant has not been reported in relation to NDDs. Protein modeling provided another line of evidence proving the pathogenicity of the novel variant.

Conclusion: Our findings indicate that the p.R86M variant may disrupt normal protein function by changing its structure and probably its interaction, potentially leading to the observed neurodevelopmental phenotypes. This study highlights the first link between the PRPF8 variant and NDDs, suggesting a distinct role for specific PRPF8 variants in the etiology of NDDs. These results warrant further investigation into the mechanisms by which PRPF8 variants contribute to NDDs, emphasizing the need for comprehensive genetic screening in families with unexplained neurodevelopmental conditions.

Keywords: autism spectrum disorder; intellectual disability; neurodevelopmental disabilities; retinitis pigmentosa; spliceosome.

FIGURE 1

The clinical phenotype of (A) proband, (B) affected sister, (C, D) affected aunt, (E) affected family members.

FIGURE 2

Family pedigree. Affected individuals are marked as black squares and the carriers of genetic variation in PRPF8 are marked by black dot.

FIGURE 3

Protein modeling results: Here, we examined a change of the amino acid from arginine to methionine at position 86. The wild‐type protein is shown in blue on the left, while the mutated protein is displayed in red on the right. At the bottom, the superimposed states of the two proteins are presented, revealing a root‐mean‐square deviation (RMSD) of 9.727 Å when comparing these two structures. The two spheres, one yellow and one green, indicate position 86 in the two proteins. The protein images were obtained from https://310.ai/copilot.

FIGURE 4

The c.257G>T variant compared to other reported variants, which is located in the MPN domain.