Intellectual disability
Gene: PRPF8

PRPF8 (pre-mRNA processing factor 8)
EnsemblGeneIds (GRCh38): ENSG00000174231
EnsemblGeneIds (GRCh37): ENSG00000174231
OMIM: 607300, Gene2Phenotype
PRPF8 is in 6 panels

3 reviews

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.
Created: 30 Jan 2023, 5:50 p.m. | Last Modified: 30 Jan 2023, 5:50 p.m.

Panel Version: 4.53

Created: 30 Jan 2023, 5:50 p.m.
Last Modified: 30 Jan 2023, 5:50 p.m.
Panel version: 4.53

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

Associated with Retinitis pigmentosa 13 (OMIM:600059) in OMIM, but not with PRPF8-related developmental disorder (monoallelic) and as a both RD and IF Gen2Phen gene for PRPF8-related developmental disorder (monoallelic). PMID: 35543142 reports 14 PRPF8 variants in unrelated cases (12/14 variants were confirmed as de novo). Intellectual disability was observed in 13/14 of these cases and seizures were evident in 4/14 cases.
Created: 24 May 2022, 1:36 p.m. | Last Modified: 24 May 2022, 1:36 p.m.

Panel Version: 3.1587

Comment on phenotypes: Gen2Phen phenotype: PRPF8-related developmental disorder (monoallelic) in addition to Retinitis pigmentosa 13
Created: 24 May 2022, 1:30 p.m. | Last Modified: 24 May 2022, 1:30 p.m.

Panel Version: 3.1587

Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Created: 24 May 2022, 1:28 p.m. | Last Modified: 24 May 2022, 1:28 p.m.

Panel Version: 3.1586

Created: 24 May 2022, 1:28 p.m.
Last Modified: 24 May 2022, 1:28 p.m.
Panel version: 3.1587

Konstantinos Varvagiannis (Other)

I don't know

A recent study suggests that heterozygous PRPF8 variants are associated with a syndromic form of DD/ID, in some cases epilepsy with heterogeneous other clinical findings. However the authors acknowledge that not all variants within their cohort may be pathogenic (5 VUSs using ACMG criteria) and that conclusive evidence may necessitate functional studies.

Heterozygous variants (typically clustering in exon 42) have been reported to cause a non-syndromic form of RP with variable expressivity and incomplete penetrance (Retinitis pigmentosa 13, MIM # 600059) .

Overall consider inclusion with amber rating.

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O'Grady et al. (2022 - PMID: 35543142) describe the phenotype of 14 unrelated individuals with heterozygous, mostly de novo, missense and pLoF variants in PRPF8.

Nearly all had some degree of global developmental delay or ID (13/14). 6/14 had a diagnosis of ASD. Seizures were reported in 4 or 5 subjects. Other features included short stature (6/14), abnormal gait, cardiac anomalies and somewhat overlapping facial features (11/14). Ages ranged from 4 - 19 years (median : 9y).

PRPF8 encodes a component of the spliceosomes which in turn are involved in removal of introns from mRNA precursors. The gene is ubiquitously expressed with expression within brain being highest in cerebral cortex, basal ganglia and cerebellum (Refs. provided).

Individuals were investigated with exome sequencing (12/14) or an autism/ID panel of >2500 genes (likely application of virtual panel on exome data).

13 individuals harbored a missense SNV and 1 further had a frameshift variant. In 12 individuals the variant had occurred de novo. 1 individual had inherited the variant from a possibly mosaic parent, while for 1 further a single parental sample was available.

PRPF8 is intolerant to both missense (Z = 8.28) and pLoF variants (pLI : 1). Variants in 5 individuals were formally classified as VUS while 2 variants were present in gnomAD.

Additional findings (CNVs/SNVs) were reported, in some cases possibly of relevance.

As the authors discuss, heterozygous pathogenic missense SNVs cause (and account for ~2-3% of) non-syndromic AD retinitis pigmentosa with variable expressivity and incomplete penetrance. Variants for this phenotype are typically missense - although nonsense ones have also been reported - clustering within ex42 (of 43) encoding the MPN domain (aa 2103-2335 / NP_006436) and weakening interaction with 2 other spliceosomal proteins.

Variants in the present study occurred throughout the gene. Although not universally assessed within the cohort, only one participant had RP (in this case variant within the MPN domain).

There were no variant studies performed.

Animal models: the authors cite a study by Graziotto et al (2011 - PMID: 20811066) where knock-in mice for a missense variant in ex42 displayed defects of the retinal pigment epithelium. A zebrafish ko model also cited (Keightley et al, 2013 - PMID: 23714367) displayed widespread apoptosis in brain and spinal cord.

The authors cite a previous bioinformatic study identifying PRPF8 as a major hub connecting gene-interaction networks for NDDs (Casanova et al, 2018 - PMID: 30420816) as well as 2 studies demonstrating enrichment of variants in individuals with NDDs compared to controls (da Silva Montenegro et al, 2020 - PMID: 31696658, Karczewski et al, 2020 - PMID: 32461654).
Sources: Literature
Created: 19 May 2022, 2:04 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Global developmental delay; Intellectual disability; Seizures; Autism; Retinitis pigmentosa 13, MIM # 600059

Publications

35543142

Created: 19 May 2022, 2:04 p.m.

Panel version: 3.1576

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Sources

Expert Review Green
NHS GMS

Phenotypes

PRPF8-related developmental disorder (monoallelic)
Retinitis pigmentosa 13, OMIM:600059

OMIM

607300

Clinvar variants

Variants in PRPF8

Penetrance

unknown

Publications

Panels with this gene

History Filter Activity

31 Jan 2023, Gel status: 3

Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag Q2_22_rating was removed from gene: PRPF8.

30 Jan 2023, Gel status: 3

Added New Source, Added New Source, Set mode of inheritance, Status Update

Arina Puzriakova (Genomics England Curator)

Source NHS GMS was added to PRPF8. Source Expert Review Green was added to PRPF8. Mode of inheritance for gene PRPF8 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

24 May 2022, Gel status: 2