PMID: 35138024

Gene: PRPF4

HGNC: 17349

Disease: retinitis pigmentosa 70

MONDO: 0014400

InheritancePattern: autosomal dominant

Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,500 and 1 in 27,000). The proportion of that incidence made up by the specific form caused by variants in PRPF4 is not clear.

Penetrance: Known disease-causing alleles appear to be incompletely penetrant (PMID: 25383878).

Note: No variants found in PRPF4 in affected patients.

PMID: 24959063

Gene: PRPF4

HGNC: 17349

Disease: retinitis pigmentosa 70

MONDO: 0014400

InheritancePattern: autosomal dominant

Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,500 and 1 in 27,000). The proportion of that incidence made up by the specific form caused by variants in PRPF4 is not clear.

Penetrance: Known disease-causing alleles appear to be incompletely penetrant (PMID: 25383878).

Case#: Benaglio_2014_Proband_001-417, sex not reported, age not reported, national origin German

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband has been diagnosed with autosomal dominant retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in the proband consisted of screening either by Sanger sequencing of 90% of known adRP genes, by genotyping microarray of known RP variants, or sequencing-based genotyping of RHO, RDS, PRPF31, RP1, PRPF8, IMPDH1, NRL, PRPF3, NR2E3, and SNRNP200.

CaseMethod1: next-generation sequencing of PRPF4 and EFTUD2 genes

CaseMethod2: Sanger sequencing of the coding regions of NHP2L1 and AAR2

CaseGenotypingMethod: Genotyping of the proband initially consisted of either Sanger sequencing of 90% of known adRP genes, genotyping microarray of known RP variants, or sequencing-based genotyping of RHO, RDS, PRPF31, RP1, PRPF8, IMPDH1, NRL, PRPF3, NR2E3, and SNRNP200. Subsequent genotyping was performed by next-generation sequencing of PRPF4 and EFTUD2 genes and Sanger sequencing of the coding regions of NHP2L1 and AAR2.

Variant: The proband harbors the NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) variant in the heterozygous state.

ClinVar ID: 865751

gnomAD: The NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) variant is found in gnomAD v4.1.0 at a frequency of 0.00006609 (90 alleles / 1180038 total alleles, with 0 homozygotes) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/9-113283207-C-G?dataset=gnomad_r4

VariantEvidence: NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) is a missense variant located 5 bp from the 3' end of exon 5 with no direct evidence of an abnormal impact on the PRPF4 protein.

CaseAddInfo: The proband has an affected sibling who also harbors the variant.

CasePMIDs: N/A

Case#: Chen_2014_Proband_S01, male, age 20 years at onset, age 53 years at time of report, family origin reported as Chinese

CasePresentingHPOs: Nyctalopia HP:0000662, Constriction of peripheral visual field HP:0001133, Severely reduced visual acuity HP:0001141, Undetectable electroretinogram HP:0000550, Retinal degeneration HP:0000546, Macular degeneration HP:0000608, Optic disc pallor HP:0000543, Attenuation of retinal blood vessels HP:0007843, Pigmentary retinopathy HP:0000580

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa. Patient fibroblasts showed 92.58% decreased expression of PRPF4.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in the proband included next-generation sequencing targeted to a large number of known variants in all known retinal disease-related genes.

CaseMethod1: next-generation sequencing

CaseMethod2: Sanger sequencing of PRPF4

CaseGenotypingMethod: Genotyping of the proband included next-generation sequencing targeted to a large number of known variants in all known retinal disease-related genes, followed by Sanger sequencing analysis of all coding regions of PRPF4.

Variant: The proband harbors the NM_004697.4(PRPF4):c.-114_-97del variant in the heterozygous state.

ClinVar ID: 143058

gnomAD: The NM_004697.4(PRPF4):c.-114_-97del variant is found in gnomAD v4.1.0 at a frequency of 0.0003297 (13 alleles / 39430 total alleles, with 0 homozygotes) in the East Asian population https://gnomad.broadinstitute.org/variant/9-113275629-TTGTCAGTGACGCACTTCC-T?dataset=gnomad_r4

VariantEvidence: NM_004697.4(PRPF4):c.-114_-97del is a deletion variant within the 5' UTR that disrupts the beginning of the transcribed region. Luciferase assay indicates that the ability of the PRPF4 promoter to activate transcription of the reporter gene was significantly decreased by the variant, which disrupted binding sites for the c-Ets-1 and GR-alpha transcription factors and matched the 93% decrease in PRPF4 expression seen in the patient blood cells (Figure 3).

CaseAddInfo: The proband has an unaffected son who does not harbor the variant.

CasePMIDs: N/A

ExperimentName: "Variant overexpression in zebrafish causes defects in visual function."

NonHumanModel: Danio rerio

GeneAlteration: The model animals have been subjected to microinjection of PRPF4 mRNA (either wild-type or harboring the p.Pro315Leu variant), with expression levels comparable to the endogenous gene.

ModelPhenotype: Photoreceptor layer loss on macular OCT HP:0030609, Inner retinal layer loss on macular OCT HP:0030620, Photoreceptor outer segment loss on macular OCT HP:0030610

HumanPhenotype: Constriction of peripheral visual field HP:0001133, Reduced visual acuity HP:0007663,, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654. Retinal degeneration HP:0000546, Macular degeneration HP:0000608, Optic disc pallor HP:0000543, Attenuation of retinal blood vessels HP:0007843, Pigmentary retinopathy HP:0000580

ModelEvidence: The variant causes severely disrupted photoreceptors in the retina (Figure 5D), reduced rhodopsin staining (rod marker) in the IS/OS layer (Figures 5E-5J) and other deformities such as malformed brains, short trunks, cardiac edema and curved body axis, at higher levels than in the wild-type control (Figures 5B and 5C). The retinal transcripts opn1lw1, gnat2, rs1, snrpg, prph2b, gnb3, and rho were decreased in the variant-expressing zebrafish (Figure 5K), while the splicing factor transcripts prpf4, prpf3, prpf31, prpf6, prpf8, snrnp200, eftud2, and sart1 were increased (Figures 5A, 5L).

ModelVariant: This model introduced the disease-associated variant NM_001244926.2(PRPF4):c.941C>T (p.Pro314Leu) in the heterozygous state (ClinVar ID: 143057).

Case#: Chen_2014_Proband_AD01-II:3, male, age 15 years at time of first exam for poor night vision, age 58 years at time of report, family origin reported as Han Chinese

CasePresentingHPOs: Nyctalopia HP:0000662, Constriction of peripheral visual field HP:0001133, Reduced visual acuity HP:0007663, Cataract HP:0000518, Retinal degeneration HP:0000546, Macular degeneration HP:0000608, Optic disc pallor HP:0000543, Attenuation of retinal blood vessels HP:0007843, Pigmentary retinopathy HP:0000580, Central thinning of the outer nuclear layer of the retina HP:6000367, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654

CaseHPOFreeText: The proband has been diagnosed with autosomal dominant retinitis pigmentosa, with features including complete loss of outer/inner segments (OS/IS) by OCT. Patient fibroblasts showed increased expression of PRPF3, PRPF6, PRPF8, PRPF31, EFTUD2, SART1, and PRPF4 itself.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in the proband included next-generation sequencing targeted to a large number of known variants in all known retinal disease-related genes.

CaseMethod1: next-generation sequencing

CaseMethod2: Sanger sequencing of PRPF4

CaseGenotypingMethod: Genotyping of the proband included next-generation sequencing targeted to a large number of known variants in all known retinal disease-related genes, followed by Sanger sequencing analysis of all coding regions of PRPF4.

Variant: The proband harbors the NM_001244926.2(PRPF4):c.941C>T (p.Pro314Leu) variant in the heterozygous state.

ClinVar ID: 143057

gnomAD: The NM_001244926.2(PRPF4):c.941C>T (p.Pro314Leu) variant is found in gnomAD v4.1.0 at a frequency of 0.000003390 (4 alleles / 1179980 total alleles, with 0 homozygotes) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/9-113288183-C-T?dataset=gnomad_r4

VariantEvidence: NM_001244926.2(PRPF4):c.941C>T (p.Pro314Leu) is a missense variant. When over-expressed in zebrafish, the variant causes severely disrupted photoreceptors in the retina and other deformities such as malformed brains, short trunks, cardiac edema and curved body axis, unlike the wild-type control.

CaseAddInfo: The proband has two similarly affected siblings (with onset in their 20's) and an unaffected child (approximately age 10 years) who also harbor the variant.

CasePMIDs: N/A

PMID: 24419317

Gene: PRPF4

HGNC: 17349

Disease: retinitis pigmentosa 70

MONDO: 0014400

InheritancePattern: autosomal dominant

Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,500 and 1 in 27,000). The proportion of that incidence made up by the specific form caused by variants in PRPF4 is not clear.

Penetrance: Known disease-causing alleles appear to be incompletely penetrant (PMID: 25383878).

ExperimentName: Altered pattern of splicing speckles in patient fibroblasts harboring a heterozygous p.Pro315Leu variant in PRPF4

PatientCell: CL:0000057 (fibroblast)

GeneFunction: GO:0000398 (mRNA splicing, via spliceosome)

GeneAlteration: Cells harbor a heterozygous p.Pro315Leu variant in PRPF4.

FunctionalEvidence: Patient cells harboring the variant exhibit a much higher level of endogenous marker of splicing speckles (SC-35) with a diffused distribution rather than a pattern of distinct speckles (Figures 4B and 4C). RT-PCR showed increased expression of SRSF1 and SRSF2 as well (Figure 4A). Collectively, the patient cells harboring the variant show molecular evidence of disrupted splicing.

FAVariants: The model harbors the NM_001244926.2(PRPF4):c.941C>T (p.Pro314Leu) variant in the heterozygous state (ClinVar ID: 143057).

ExperimentName: PRPF4 physically interacts with PRPF3.

InteractingGene: PRPF3 (HGNC:17348)

InteractionType: Physical

InteractionMethod: Co-immunoprecipitation

InteractionEvidence: Immunoprecipitation of endogenous PRPF3 from HeLa cell nuclear extracts pulled down PRPF4 (Figures 5 and 6).

PMID: 9328476

Gene: PRPF4

HGNC: 17349

Disease: retinitis pigmentosa 70

MONDO: 0014400

InheritancePattern: autosomal dominant

Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,500 and 1 in 27,000). The proportion of that incidence made up by the specific form caused by variants in PRPF4 is not clear.

Penetrance: Known disease-causing alleles appear to be incompletely penetrant (PMID: 25383878).

ExperimentName: "Prpf4 silencing in zebrafish causes defects in visual function."

NonHumanModel: Danio rerio

GeneAlteration: The model animals have been subjected to morpholino-based knockdown of Prpf4, the zebrafish ortholog of human PRPF4.

ModelPhenotype: Nystagmus HP:0000639, Abnormality of ocular smooth pursuit HP:0000617

HumanPhenotype: Constriction of peripheral visual field HP:0001133, Reduced visual acuity HP:0007663,, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654. Retinal degeneration HP:0000546, Macular degeneration HP:0000608, Optic disc pallor HP:0000543, Attenuation of retinal blood vessels HP:0007843, Pigmentary retinopathy HP:0000580

ModelEvidence: Morpholino-based incomplete knockdown of the Prpf4 gene circumvents the lethality of complete silencing and causes optokinetic nystagmus with a significantly reduced number of saccades (Fig. 5B, 5C, 5D). Immunohistochemistry showed that retinal morphology showed mostly normal retinal layering but decreased rhodopsin staining in the photoreceptor cell layer (Figs. 5E–5H). Photoreceptor outer segments were primarily affected, but with unaffected cell body morphology (Figs. 5I and 5J). This phenotype was a complete match for the zebrafish with Prpf31 loss/. Semi-quantitative RT–PCR analysis of the RP-relevant transcripts opn1lw1, opn1mw1, gnat2, irx6a, rx3, crx and rhodopsin as well as the controls gapdh and lsm7 showed a very similar pattern of down-regulation in both Prpf31- and Prpf4-deficient animals (Fig. 5W). The phenotype was dose-dependent and could be rescued by co-injection of Prpf4 mRNA (Fig. S2).

ModelVariant: This model did not introduce a disease-associated variant known from an affected human patient, but rather studied the effects of heterozygous loss of the gene product.

PMID: 21051334

Gene: PRPF4

HGNC: 17349

Disease: retinitis pigmentosa 70

MONDO: 0014400

InheritancePattern: autosomal dominant

Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,500 and 1 in 27,000). The proportion of that incidence made up by the specific form caused by variants in PRPF4 is not clear.

Penetrance: Known disease-causing alleles appear to be incompletely penetrant (PMID: 25383878).

PMID: 38184646

Gene: PRPF4

HGNC: 17349

Disease: retinitis pigmentosa 70

MONDO: 0014400

InheritancePattern: autosomal dominant

Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,500 and 1 in 27,000). The proportion of that incidence made up by the specific form caused by variants in PRPF4 is not clear.

Penetrance: Known disease-causing alleles appear to be incompletely penetrant (PMID: 25383878).

Case#: Dueñas Rey_2024_Proband_F11, sex and age not reported, part of cohort from Center for Medical Genetics Ghent

CasePresentingHPOs: Rod-cone dystrophy HP:0000510, Intellectual disability HP:0001249

CaseHPOFreeText: The proband has been diagnosed with rod-cone dystrophy and clinical signs of Bardet-Biedl syndrome. Intellectual disability may be part of the phenotype.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in the proband consisted of whole exome sequencing with analysis focused on the 5' UTR regions of 378 genes highly expressed in the retina.

CaseMethod1: whole exome sequencing

CaseMethod2: Sanger sequencing of the coding regions of PRPF4

CaseGenotypingMethod: Genotyping of the proband initially consisted of whole exome sequencing, followed by Sanger sequencing of the coding regions of PRPF4.

Variant: The proband harbors the NM_001244926.2:c.-6C>T variant in the heterozygous state.

CAID: CA2579423618

gnomAD: The NM_001244926.2:c.-6C>T variant is found in gnomAD v4.1.0 at a frequency of 8.400e-7 (4 alleles / 1178930 total alleles, with 0 homozygotes) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/9-113275738-C-T?dataset=gnomad_r4

VariantEvidence: NM_001244926.2:c.-6C>T is a 5' UTR variant located within the Kozak consensus sequence but has no direct evidence of an abnormal impact on PRPF4 expression.

CaseAddInfo: The proband has apparently unaffected parents.

CasePMIDs: N/A

Selection A- Gene with same function implicated in disease

ExperimentName: PRPF4 is a U4/U6 small nuclear ribonucleoprotein component that functions in mRNA splicing.

GOterm: GO:0000398 (mRNA splicing, via spliceosome)

FunctionalEvidence: PRPF4, PRPF3, PRPF31, and PRPF8 are all splicing factors involved in mRNA processing and are encoded by genes that harbor variants associated with retinitis pigmentosa.

HGNC: HGNC:17348 (PRPF3, retinitis pigmentosa 18), HGNC:15446 (PRPF31, retinitis pigmentosa 11), HGNC:17340 (PRPF8, retinitis pigmentosa 13)

GeneEvidence: PRPF3 harbors variants that cause retinitis pigmentosa 18 (PMID: 11773002), PRPF31 harbors variants that cause retinitis pigmentosa 11 (PMID: 12444105), and PRPF8 harbors variants that cause retinitis pigmentosa 13 (PMID: 7951236).

SharedGeneImplication: PRPF4, PRPF3, PRPF31, and PRPF8 are encode splicing factors involved in mRNA processing.

PMID: 9257651

Gene: PRPF4

HGNC: 17349

Disease: retinitis pigmentosa 70

MONDO: 0014400

InheritancePattern: autosomal dominant

Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,500 and 1 in 27,000). The proportion of that incidence made up by the specific form caused by variants in PRPF4 is not clear.

Penetrance: Known disease-causing alleles appear to be incompletely penetrant (PMID: 25383878).

PRPF4, PRPF3, PRPF31, and PRPF8 are all splicing factors involved in mRNA processing and are encoded by genes that harbor variants associated with retinitis pigmentosa.

PMID: 31654038

PMID: 27302685

review article

Case#: Linder_2014_Proband_RP-106, female, age 20 years at time of onset / first visual complaints, age 73 year at time of report, family origin not reported

CasePresentingHPOs: Nyctalopia HP:0000662, Constriction of peripheral visual field HP:0001133, Cataract HP:0000518, Attenuation of retinal blood vessels HP:0007843, Bone spicule pigmentation of the retina HP:0007737, Undetectable dark-adapted electroretinogram HP:0030474, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654

CaseHPOFreeText: The proband has been diagnosed with sporadic retinitis pigmentosa. Phenotypes included pale papillae in fundus.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in the proband was not clearly described, but she was part of a cohort of patients with no previously-identified retinitis pigmentosa-associated variants.

CaseMethod1: SSCP analysis of 14 PCR-amplified PRPF4 exons

CaseMethod2: Sanger sequencing of PRPF4

CaseGenotypingMethod: Previous testing in the proband was not clearly described, but she was part of a cohort of patients with no previously-identified retinitis pigmentosa-associated variants. SSCP was performed on each of 14 PCR-amplified exons of PRPF4, followed by Sanger sequencing analysis.

Variant: The proband harbors the NM_001244926.2(PRPF4):c.572G>A (p.Arg191His) variant in the heterozygous state.

ClinVar ID: 967144

gnomAD: The NM_001244926.2(PRPF4):c.572G>A (p.Arg191His) variant is found in gnomAD v4.1.0 at a frequency of 0.00004999 (3 / 60014, with 0 homozygotes) in the Admixed American population https://gnomad.broadinstitute.org/variant/9-113283400-G-A?dataset=gnomad_r4

VariantEvidence: NM_001244926.2(PRPF4):c.572G>A (p.Arg191His) is a missense variant. When overexpressed in zebrafish, the variant fails to rescue the lethality of Prpf4 silencing, unlike overexpression of the wild-type gene (Figure 2). Co-immunoprecipitation experiments show that the variant localizes normally but disrupts interaction with PRPF3 (Figure 3) and blocks PRPF4 integration into snRNP complexes (Figure 4).

CaseAddInfo: The proband has two daughters at ages 52 and 54 years who harbor the variant but showed no retinal abnormalities in ophthalmological examinations.

CasePMIDs: N/A

PMID: 25383878

Gene: PRPF4

HGNC: 17349

Disease: retinitis pigmentosa 70

MONDO: 0014400

InheritancePattern: autosomal dominant

Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,500 and 1 in 27,000). The proportion of that incidence made up by the specific form caused by variants in PRPF4 is not clear.

Penetrance: Known disease-causing alleles appear to be incompletely penetrant (PMID: 25383878).

PMID: 16723661

Gene: PRPF4

HGNC: 17349

Disease: retinitis pigmentosa 70

MONDO: 0014400

InheritancePattern: autosomal dominant

Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,500 and 1 in 27,000). The proportion of that incidence made up by the specific form caused by variants in PRPF4 is not clear.

Penetrance: Known disease-causing alleles appear to be incompletely penetrant (PMID: 25383878).

Zebrafish harboring an engineered mutation in the prpf4 gene exhibit enhanced brain and spinal cord apoptosis. The mechanism is loss-of-function. Matches the patients?

PMID: 30174136

PMID: 37264419

Gene: PRPF4

HGNC: 17349

Disease: retinitis pigmentosa 70

MONDO: 0014400

InheritancePattern: autosomal dominant

Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,500 and 1 in 27,000). The proportion of that incidence made up by the specific form caused by variants in PRPF4 is not clear.

Penetrance: Known disease-causing alleles appear to be incompletely penetrant (PMID: 25383878).

Case#: Xiao_2023_Family_2_Proband, male, age 0.5 years, family origin reported as from Yi ethnic group from Yunnan, China

CasePresentingHPOs: Infantile onset HP:0003593, Pigmentary retinopathy HP:0000580, Mild myopia HP:0025573

CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa with onset at 0.3 years of age.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in the proband consisted of whole exome sequencing.

CaseMethod1: whole exome sequencing

CaseMethod2: Sanger sequencing of the coding regions of PRPF4

CaseGenotypingMethod: Genotyping of the proband initially consisted of whole exome sequencing, followed by Sanger sequencing of the coding regions of PRPF4.

Variant: The proband harbors the NM_001244926.2(PRPF4):c.1270G>A (p.Gly424Ser) variant in the heterozygous state.

ClinVar ID: 1395419

gnomAD: The NM_001244926.2(PRPF4):c.1270G>A (p.Gly424Ser) variant is found in gnomAD v4.1.0 at a frequency of 0.00008729 (103 alleles / 1180028 total alleles, with 0 homozygotes) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/9-113290914-G-A?dataset=gnomad_r4

VariantEvidence: NM_001244926.2(PRPF4):c.1270G>A (p.Gly424Ser) is a missense variant with no direct evidence of an abnormal impact on the PRPF4 protein.

CaseAddInfo: The proband has apparently unaffected parents.

CasePMIDs: N/A

Case#: Benaglio_2014_Proband_001-417, sex not reported, age not reported, national origin German

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband has been diagnosed with autosomal dominant retinitis pigmentosa.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing in the proband consisted of screening either by Sanger sequencing of 90% of known adRP genes, by genotyping microarray of known RP variants, or sequencing-based genotyping of RHO, RDS, PRPF31, RP1, PRPF8, IMPDH1, NRL, PRPF3, NR2E3, and SNRNP200.

CaseMethod1: next-generation sequencing of PRPF4 and EFTUD2 genes

CaseMethod2: Sanger sequencing of the coding regions of NHP2L1 and AAR2

CaseGenotypingMethod: Genotyping of the proband initially consisted of either Sanger sequencing of 90% of known adRP genes, genotyping microarray of known RP variants, or sequencing-based genotyping of RHO, RDS, PRPF31, RP1, PRPF8, IMPDH1, NRL, PRPF3, NR2E3, and SNRNP200. Subsequent genotyping was performed by next-generation sequencing of PRPF4 and EFTUD2 genes and Sanger sequencing of the coding regions of NHP2L1 and AAR2.

Variant: The proband harbors the NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) variant in the heterozygous state.

ClinVar ID: 865751

gnomAD: The NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) variant is found in gnomAD v4.1.0 at a frequency of 0.00006609 (90 alleles / 1180038 total alleles, with 0 homozygotes) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/9-113283207-C-G?dataset=gnomad_r4

VariantEvidence: NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) is a missense variant located 5 bp from the 3' end of exon 5 with no direct evidence of an abnormal impact on the PRPF4 protein.

CaseAddInfo: The proband has an affected sibling who also harbors the variant.

CasePMIDs: N/A

PMID: 18334927