PMID: 24938718

Gene: TOPORS

Case: Case_47

CasePresentingHPOsFreeText: RP, A cohort of 168 unrelated Korean patients with IRD was recruited from the Department of Ophthalmology, Seoul National University Hospital (SNUH), from October 2008 to January 2019. A detailed family history was obtained from each patient to construct a pedigree. All patients underwent a detailed ophthalmic history and ophthalmic examinations, including best-corrected visual acuity, slit-lamp biomicroscopy, fundus photography, optical coherence tomography, fluorescein angiography, visual field tests, and full-field electroretinograms. Clinical diagnosis was determined by at least two retinal specialists (DJM and UCP).

CasePreviousTesting: WES

CaseGenotypingMethod: WES was performed at the Genomics core facility of the Center for BioMarkers (SNUH, South Korea) using an Illumina NextSeq500

Variant: c.2514_2515del, p.N838fs

ClinVarID: or CAID: CA2573335125

gnomAD:

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

PMID: 33691693

Gene: TOPORS

FamilyName: Selmer_Family

FamilyPresentingHPOFreeText: autosomal dominant pericentral retinal dystrophy (adPRD). Sixteen individuals (aged 23–78 years) were ophthalmologically examined as part of this project and 10 of them were assigned a diagnosis of PRD (Table 1). The ophthalmological examinations revealed an atypical form of retinitis pigmentosa (RP), which we prefer to call adPRD. Compared with classical RP, this phenotype has a favourable prognosis

CountryOrigin: Norway

FamilyPreviousTesting: We performed a genome-wide linkage analysis followed by sequencing of a candidate gene to identify the mutation causing the disease.

FamilyMethod1:

FamilyMethod2:

FamilyGenotypingMethod: Mutations in the RHO, RP1, RDS and IMPDH1 genes as a cause of adRP in this family were excluded in a separate study published elsewhere (Grøndahl et al. 2007). Genotyping was performed using the Affymetrix GeneChip® Human Mapping 10 K 2.0 array (Matsuzaki et al. 2004), according to the supplier’s protocol. All three exons of the TOPORS gene, including exon–intron boundaries, were sequenced.

Affected:

Unaffected:

Segregations:

PublishedLOD: 7.3

AddSegregationInfo: Preliminary results of linkage analysis showed a linkage peak with a LOD (logarithm of the odds) score of 2.6 covering the recently reported adRP gene TOPORS. This gene was sequenced in 19 family members and a missense mutation c.1205a>c was identified in exon 3 in all affected members, leading to a p.Q402P amino acid substitution. The mutation showed complete co-segregation with the disease (Fig. 1) in all members tested, and linkage analysis yielded a LOD score of 7.3, assuming complete penetrance and a mutation frequency of 0.001.

ProbandLabel: Selmer_Proband

Variant:

gnomAD: absent in gnomAD

CAID: CA373170940

PMID: 19183411

Gene: TOPORS

PMID: 33576794

Gene: TOPORS

Case: AD64, 43 year old female

CasePresentingHPOsFreeText: All probands and their affected and unaffected relatives were enrolled at the Retinal Dystrophy Unit of ASST Santi Paolo e Carlo Hospital, University of Milan (Italy), from 2011 to early 2019. They underwent detailed clinical examination, including best-corrected visual acuity, slit-lamp examination, visual field analysis, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), and dark- and light-adapted electroretinogram (ERG). Diagnosis of RP was based on typical clinical signs (optic disc pallor, bone spicule pigmentation, retinal vessel attenuation), characteristic full-field electoretinographic patterns, varying from reduced A- and B-wave amplitudes in early stages to nondetectable ERG in advanced stages (as established by the International Society for Clinical Electrophysiology of Vision), visual field constriction, and particular SD-OCT and FAF patterns. Patients suspected to have US (retinitis pigmentosa and sensorineural bilateral hearing loss) also underwent complete audiometric evaluation.

Detailed demographic data and family history were recorded by interview. For each proband, the disease (RP or US) and the inheritance model (AD-RP, AR-RP, or XL-RP) were suspected on the basis of clinical data and pedigree, when available.

CasePreviousTesting:

CaseGenotypingMethod: DNA was extracted using a commercial kit (E.Z.N.A. Blood DNA kit; Omega Bio-Tek, Norcross, GA, USA) and analyzed by next-generation sequencing (NGS) on an Illumina MiSeq personal sequencer (Illumina, San Diego, CA, USA) using an in-house bioinformatics pipeline as previously described.9,10

The gene panels were periodically updated with new disease-associated genes reported in the literature, so that four different custom NGS panel releases were used in the 8-year period of observation. The list of genes in the latest multigene panel (used to test 267 samples between 2017 and 2019) is shown in Supplementary Table S1; a comparison of genes included in the other three panels can be found in Supplementary Table S2. All genetic variants were validated by Sanger sequencing using a Beckman Coulter CEQ 8000 sequencer (Beckman Coulter, Milan, Italy). Sanger sequencing was also used for family segregation studies when additional family members were available

Variant: c.2539C>T, p.(Arg847*)

ClinVarID: or CAID: CA353607

gnomAD: absent

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PreviouslyPublished:

VariantEvidence:

PMID: 17924349

Gene: TOPORS

Case: German

CasePresentingHPOsFreeText: We report mutations in the gene for topoisomerase I–binding RS protein (TOPORS) in patients with autosomal dominant retinitis pigmentosa (adRP)

CasePreviousTesting: Sequencing of the coding regions of all other genes in the RP31 critical region revealed only nonpathogenic sequence variants.

CaseGenotypingMethod:

Variant: a 2-bp deletion (c.2552_2553delGA) in exon 3 leading to p.Arg851fs

ClinVarID: or CAID: CA645509428

gnomAD: absent

VariantEvidence: c.2556_2557del p.Glu852AspfsTer20, check for NMD

Case: French Canadian

CasePresentingHPOsFreeText: We report mutations in the gene for topoisomerase I–binding RS protein (TOPORS) in patients with autosomal dominant retinitis pigmentosa (adRP)

CasePreviousTesting: Sequencing of the coding regions of all other genes in the RP31 critical region revealed only nonpathogenic sequence variants.

CaseGenotypingMethod:

Variant: heterozygous 1-bp insertion (c.2474_2475insA) in exon 3; this frameshift mutation segregates with the affected status and is predicted to result in a premature stop codon (p.Tyr825fs)

ClinVarID: or CAID: CA913185045

gnomAD: absent

VariantEvidence: NM_005802.5:c.2474dup (p.Tyr825Ter), check for NMD. LOD score for segregation of variant in this family is reported in PMID: 16189705

Case: 9237

CasePresentingHPOsFreeText: RP, A cohort of 266 patients with visual impairment diagnosed by different medical centers in the Netherlands were included in this study. The specific eye disorders were diagnosed by expert ophthalmologists based on appropriate clinical examinations.

CasePreviousTesting: WES

CaseGenotypingMethod: Sequencing of the exome was performed after the participants were counseled by a clinical geneticist at one of the medical university centers located in the Netherlands. DNA was extracted from peripheral blood using standard procedures. In all 266 cases, exome enrichment was performed using Agilent's SureSelect XT Human All Exon V4 (Agilent Technologies, Santa Clara, CA, USA). For 48 cases, next-generation sequencing was performed using a 5500xl SOLiD System (Life Technologies). All reported single-nucleotide variants have been validated by Sanger sequencing

Variant: c.2550_2553del, p.(Asp850fs)

ClinVarID: or CAID: CA658821678

gnomAD: absent

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

PMID: 28224992

Gene: TOPORS

Case: RFS169_Proband

CasePresentingHPOsFreeText: The prospectus was a 31-year-old Caucasian male whose major complaint was difficulty going down steps and curbs in dim light or at night. He was aware that his peripheral vision was poor and reported frequent inability to locate objects. His sister, mother, maternal aunt, maternal grandfather, maternal great-grandfather, and maternal great uncle had been diagnosed with RP (Figure 1B). He reported that his mother had severe night blindness at age 20 and was now 60 years old with extremely poor vision.

CasePreviousTesting: Each proband has been previously tested for mutations in the complete coding region of CA4, CRX, FSCN2, IMPDH1, NRL, PRPF31, RDS, RHO, ROM1, and RP9. Samples were also screened for mutations in mutational “hot spots” of RP1, PRPF3, PRPF8, and NR2E3.

CaseGenotypingMethod: PCR products were treated with ExoSapIt (USB, Cleveland, OH) and sequenced unidirectionally with BigDye v1.1 (Applied Biosystems) and the primers described in Table 1. PCR product sequencing was employed to screen patient DNA for mutations in the entire coding region and flanking intron/exon junction of TOPORS.

Variant: c.G2422T nonsense change, which resulted in a p.Glu808X in family.

ClinVarID: or CAID: CA373163668

gnomAD: absent

VariantEvidence: Analysis of this mutation in eight additional family members demonstrated that this mutation tracks with disease (Figure 1).

Case: UTAD102_Proband

CasePresentingHPOsFreeText: The prospectus was a 52-year-old Hispanic male with only hand motion vision in both eyes. He had two brothers and three children diagnosed with RP (Figure 1A). Extensive bone-spicule-like pigment deposits and severely attenuated blood vessels were seen bilaterally, consistent with end stage RP. Optic disc pallor and macular retinal pigment epithelium atrophy were also present. Goldman visual fields were not possible due to the patient’s poor vision.

CasePreviousTesting: Each proband has been previously tested for mutations in the complete coding region of CA4, CRX, FSCN2, IMPDH1, NRL, PRPF31, RDS, RHO, ROM1, and RP9. Samples were also screened for mutations in mutational “hot spots” of RP1, PRPF3, PRPF8, and NR2E3.

CaseGenotypingMethod: PCR products were treated with ExoSapIt (USB, Cleveland, OH) and sequenced unidirectionally with BigDye v1.1 (Applied Biosystems) and the primers described in Table 1. PCR product sequencing was employed to screen patient DNA for mutations in the entire coding region and flanking intron/exon junction of TOPORS.

Variant: A 1 bp deletion at nucleotide 2,569 was detected (c.2569delA; p.Arg857GlyfsX9). This deletion caused a frame-shift at amino acid residue 857, and was predicted to result in the addition of eight incorrect amino acids followed by premature termination.

ClinVarID: or CAID: CA645509427

gnomAD: absent

VariantEvidence:

PMID: 18509552

Gene: TOPORS

PMID: 31736247

Gene: TOPORS

Case: EC17

CasePresentingHPOsFreeText: All probands underwent a complete ophthalmological evaluation, including best corrected visual acuity, biomicroscopy, color fundus photography, fundus autofluorescence, electrophysiological testing, and swept‐source optical coherence tomography (DRI SS OCT Triton, (TOPCON corporation)). The clinical diagnosis of a RD was made by retina specialists based on the patient's history of visual symptoms, clinical examination, retinal imaging, and electrophysiology. Clinical and family history details were collected during genetic consultation.

CasePreviousTesting:

CaseGenotypingMethod: Gene enrichment during library preparation was performed using the commercial ClearSeq Inherited Disease Panel (Agilent Technologies). This panel has a 10.5 Mb capture capacity and targets the coding exons and splicing regions of 2,742 genes involved in inherited disorders. The panel includes 199 RD‐related genes, in accordance with the Retinal Information Network (RETNET; https://sph.uth.edu/retnet/home.htm) and the Online Mendelian Inheritance in Man (OMIM) catalog (https://www.omim.org/ ) at the time of the study (accessed on September 2018). One hundred and four of these genes have been implicated exclusively in non‐syndromic RDs, 23 are associated with both syndromic and non‐syndromic forms of RDs, and 72 are involved only in syndromic RDs (Table S1).

Variant: c.2554_2557delGAGA, p.Glu852GlnfsTer13

ClinVarID: or CAID: CA270089

gnomAD: found in one european (non-finnish) genome

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

PMID: 21159800

Gene: TOPORS