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Current technologies for delivering gene testing are labour-intensive and expensive. Over the last 3 years, new high-throughput DNA sequencing techniques (next generation sequencing; NGS), with the capability to analyse multiple genes or entire genomes, have been rapidly adopted into research. This study examines the possibility of incorporating NG...
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... chose 14 patients at random who had no molecular diagnosis after this conventional testing strategy. The NGS assay of the 14 patients identified 9/14 (64%, 95% CI 38.7% to 83.6%) with variants that were highly likely to be pathogenic (table 1). Although a small number, if generalised, this would equate to a predicted pickup for pathogenic variants rate using the new technology of 80% of patients with adRP. ...
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Citations
... home.htm, Stand 04.2023) [4,11,19]. ...
Zusammenfassung
Hintergrund
Aufkommende Therapien führen zu wachsendem Interesse an hereditären Netzhauterkrankungen (engl. „inherited retinal diseases“ [IRDs]), einer heterogenen Gruppe seltener Erkrankungen, die potenziell zur Erblindung führen. Aktuell sind nur unzureichend systematische Studien zur Demografie und zum Management der IRDs in deutschen augenärztlichen Einrichtungen vorhanden.
Ziele der Arbeit
Charakterisierung der Versorgung von IRD-Patient*innen in Deutschland, Erfassung von Daten zur Diagnostik, zur systematischen Speicherung der Patient*innendaten und zur Weiterbildung in Ophthalmogenetik.
Methoden
Die anonyme Umfrage mittels Online-Fragebogen (SoSci Survey GmbH) wurde an alle deutschen Augenkliniken (Quelle: Deutsche Ophthalmologische Gesellschaft) und 3 IRD-Schwerpunktpraxen versandt. Der für die Umfrage entwickelte Katalog bestand aus 69 Fragen.
Ergebnisse
Die Antwortquote betrug 44,8 %. Fast alle Einrichtungen (93,6 %) gaben an, IRD-Patient*innen zu betreuen, jedoch unterscheiden sich universitäre und nichtuniversitäre Kliniken stark in der Patient*innenzahl. Datenbanken wurden in 60 % der universitären (UK) und 5,9 % der nichtuniversitären Kliniken (NUK) genutzt. Die Hälfte (53 %) der NUKs und 12 % der UKs gaben an, dass weniger als 20 % der betreuten Patient*innen eine molekulargenetische Diagnose erhielten. Die Antworten der Schwerpunktpraxen ähnelten denen der UKs. Patient*innen mit der mittels Voretigen Neparvovec therapierbaren RPE65 -mutationsassoziierten IRD wurden in 9 UKs betreut.
Diskussion
Die Umfrage zeigt Defizite in der Versorgung von IRDs auf. Insbesondere war der Prozentsatz von Betroffenen mit bekanntem Genotyp zwischen UKs und NUKs sehr unterschiedlich. Hier sollten gerade wegen der aufkommenden Therapien Verbesserungen initiiert werden.
... In family2, a rarely reported nonsense MERTK variant c.2194 C > T caused non-syndromic RP and maculopathy. This variant was previously only reported by O'Sullivan et al. [45] in an RP patient from a British cohort. The MERTK gene encodes MER tyrosine kinase receptor that plays crucial role in phagocytosis of retinal pigment epithelium (RPE) [46]. ...
Background
Retinitis Pigmentosa (RP) is a clinically and genetically progressive retinal dystrophy associated with severe visual impairments and sometimes blindness, the most common syndromic form of which is Usher syndrome (USH). This study aimed to further increase understanding of the spectrum of RP in the Khyber Pakhtunkhwa region of Pakistan.
Methodology
Four consanguineous families of Pashtun ethnic group were investigated which were referred by the local collaborating ophthalmologists. In total 42 individuals in four families were recruited and investigated using whole exome and dideoxy sequencing. Among them, 20 were affected individuals including 6 in both family 1 and 2, 5 in family 3 and 3 in family 4.
Result
Pathogenic gene variants were identified in all four families, including two in cone dystrophy and RP genes in the same family (PDE6C; c.480delG, p.Asn161ThrfsTer33 and TULP1; c.238 C > T, p.Gln80Ter) with double-homozygous individuals presenting with more severe disease. Other pathogenic variants were identified in MERTK (c.2194C > T, p.Arg732Ter), RHO (c.448G > A, p.Glu150Lys) associated with non-syndromic RP, and MYO7A (c.487G > A, p.Gly163Arg) associated with USH. In addition, the reported variants were of clinical significance as the PDE6C variant was detected novel, whereas TULP1, MERTK, and MYO7A variants were detected rare and first time found segregating with retinal dystrophies in Pakistani consanguineous families.
Conclusions
This study increases knowledge of the genetic basis of retinal dystrophies in families from Pakistan providing information important for genetic testing and diagnostic provision particularly from the Khyber Pakhtunkhwa region.
... In previous studies, an improved mutation-detection rate via WGS was described compared to targeted panels and WES, although the improvement varied between a few percent and 24% [1][2][3][4]7,11,[37][38][39][40]. It was found that the WGS was superior in the detection of SVs, variants in regulatory regions, and variants in GC-rich regions compared to WES [11]. ...
Inherited retinal diseases (IRDs) are a diverse set of visual disorders that collectively
represent a major cause of early-onset blindness. With the reduction in sequencing costs in recent
years, whole-genome sequencing (WGS) is being used more frequently, particularly when targeted
gene panels and whole-exome sequencing (WES) fail to detect pathogenic mutations in patients.
In this study, we performed mutation screens using WGS for a cohort of 311 IRD patients whose
mutations were undetermined. A total of nine putative pathogenic mutations in six IRD patients
were identified, including six novel mutations. Among them, four were deep intronic mutations
that affected mRNA splicing, while the other five affected protein-coding sequences. Our results
suggested that the rate of resolution of unsolved cases via targeted gene panels and WES can be
further enhanced with WGS; however, the overall improvement may be limited.
... For most routine research and diagnostic sequencing, enrichment for target sequences is typically performed to optimise the cost-benefits of reduced sequencing, analysis and data storage against the risk of missing causal variants in a few cases. Typically, DNA isolated from individuals with a suspected IRD will be sent for sequencing via a custom gene panel approach [1][2][3][4][5][6][7][8][9][10][11][12]. In cases where this is unsuccessful, a broader approach, such as whole exome (WES) or whole genome sequencing (WGS), will then be employed [13][14][15]. ...
Macular dystrophies are a group of individually rare but collectively common inherited retinal dystrophies characterised by central vision loss and loss of visual acuity. Single molecule Molecular Inversion Probes (smMIPs) have proved effective in identifying genetic variants causing macular dystrophy. Here, a previously established smMIPs panel tailored for genes associated with macular diseases has been used to examine 57 UK macular dystrophy cases, achieving a high solve rate of 63.2% (36/57). Among 27 bi-allelic STGD1 cases, only three novel ABCA4 variants were identified, illustrating that the majority of ABCA4 variants in Caucasian STGD1 cases are currently known. We examined cases with ABCA4-associated disease in detail, comparing our results with a previously reported variant grading system, and found this model to be accurate and clinically useful. In this study, we showed that ABCA4-associated disease could be distinguished from other forms of macular dystrophy based on clinical evaluation in the majority of cases (34/36)
... We therefore genetically tested 64 individuals, which identified pathogenic mutations in 18 genes, including ten novel genetic mutations (Table 1). Although patients with RP had the lowest gene detection rate, previous reports using multigene panels, next-generation sequencing, or exome sequencing have had similar findings (50% to 80%) [66,[91][92][93][94][95]. ...
The overlapping genetic and clinical spectrum in inherited retinal degeneration (IRD) creates challenges for accurate diagnoses. The goal of this work was to determine the genetic diagnosis and clinical features for patients diagnosed with an IRD. After signing informed consent, peripheral blood or saliva was collected from 64 patients diagnosed with an IRD. Genetic testing was performed on each patient in a Clinical Laboratory Improvement Amendments of 1988 (CLIA) certified laboratory. Mutations were verified with Sanger sequencing and segregation analysis when possible. Visual acuity was measured with a traditional Snellen chart and converted to a logarithm of minimal angle of resolution (logMAR). Fundus images of dilated eyes were acquired with the Optos® camera (Dunfermline, UK). Horizontal line scans were obtained with spectral-domain optical coherence tomography (SDOCT; Spectralis, Heidelberg, Germany). Genetic testing combined with segregation analysis resolved molecular and clinical diagnoses for 75% of patients. Ten novel mutations were found and unique genotype phenotype associations were made for the genes RP2 and CEP83. Collective knowledge is thereby expanded of the genetic basis and phenotypic correlation in IRD.
... Sequencing was then performed using a Next-Seq500 (Illumina, San Diego, CA) p, according to the manufacturer's protocols. Bioinformatic analyses and clinical interpretation were performed as previously described (O'Sullivan et al. 2012;Ellingford et al. 2016a). ...
Purpose:
Congenital stationary night blindness (CSNB) is a heterogeneous group of Mendelian retinal disorders that present in childhood. Biallelic variants altering the protein-coding region of the TRPM1 gene are one of the commonest causes of CSNB. Here, we report the clinical and genetic findings in 10 unrelated individuals with TRPM1-retinopathy.
Methods:
Study subjects were recruited through a tertiary clinical ophthalmic genetic service at Manchester, UK. All participants underwent visual electrodiagnostic testing and panel-based genetic analysis.
Results:
Study subjects had a median age of 8 years (range: 3-20 years). All probands were myopic and had electroretinographic findings in keeping with complete CSNB. Notably, three probands reported no night vision problems. Fourteen different disease-associated TRPM1 variants were detected. One individual was homozygous for the NM_001252024.2 (TRPM1):c.965 + 29G>A variant and a mini-gene assay highlighted that this change results in mis-splicing and premature protein termination. Additionally, two unrelated probands who had CSNB and mild neurodevelopmental abnormalities were found to carry a 15q13.3 microdeletion. This copy number variant encompasses seven genes, including TRPM1, and was encountered in the heterozygous state and in trans with a missense TRPM1 variant in each case.
Conclusion:
Our findings highlight the importance of comprehensive genomic analysis, beyond the exons and protein-coding regions of genes, for individuals with CSNB. When this characteristic retinal phenotype is accompanied by extraocular findings (including learning and/or behavioural difficulties), a 15q13.3 microdeletion should be suspected. Focused analysis (e.g. microarray testing) is recommended to look for large-scale deletions encompassing TRPM1 in patients with CSNB and neurodevelopmental abnormalities.
... 2,3 Recently, a pregnant woman requested genetic counseling for a heterozygous deletion of the whole TOPORS gene (OMIM: 609507), for which truncating variants have been reported to cause autosomal dominant retinitis pigmentosa (adRP). [4][5][6][7][8][9][10][11][12][13][14][15][16] Based on these studies, haploinsufficiency has been suggested as the molecular mechanism, implying that most truncating variants (especially those at the N-terminus, large structural variants, or copy number deletions) are pathogenic. Therefore, these CNVs may be classified as potential pathogenic variants based on the recommended criteria in 2015 by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), 17 as well as suggested by updated recommendations. ...
... Based on the HGMD database (as of January 2021), LOVD database (as of December 2021), and PubMed search (as of January 2022), 17 heterozygous truncating variants of TOPORS were reported to be causative for autosomal dominant retinopathy in 47 families, including 42 families with typical RP and five families with unclassified retinal dystrophy. [4][5][6][7][8][9][10][11][12][13][14][15][16][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] All except one variant were distributed in exon 3, which is the last exon of TOPORS. These variants were clustered in a specific region from coding residues 807 to 867 downstream of the SR/RS domain (Fig. 1A). ...
... A series of previous studies, including a prior study of ours, have demonstrated that heterozygous truncating variants of TOPORS are responsible for adRP. [4][5][6][7][8][9][10][11][12][13][14][15][16]24,[31][32][33][34][35][36][37][38][39][40][41][42][43][44] Haploinsufficiency has been suggested to be an underlying mechanism of pathogenesis in previous studies. In this study, however, systematic comparative analysis at the individual gene level based on large datasets suggests that heterozygous causative truncating variants for adRP are clustered in the 807 to 867 residues. ...
Purpose:
Heterozygous truncating variants of TOPORS have been reported to cause autosomal dominant retinitis pigmentosa (adRP). The purpose of this study was to investigate whether all heterozygous truncating variants, including copy number variants (CNVs), are pathogenic.
Methods:
TOPORS truncating variants were collected and reviewed through an in-house dataset and existing databases. Individuals with truncating variants underwent ophthalmological evaluation.
Results:
Six truncating variants were detected in seven families. Three N-terminus truncating variants were detected in three families without RP, and the other three were identified in four unrelated families with typical RP. Based on the in-house dataset and published literature, 17 truncating variants were identified in 47 families with RP. All RP-associated truncating alleles, except one, were distributed in the last exon of TOPORS and clustered in amino acid residues 807 to 867 (46/47, 97.9%). Conversely, in the gnomAD database, only one truncating allele (1/27, 3.7%) was in this region, and the others were outside (26/27, 96.3%), suggesting that the pathogenic truncating variants were significantly clustered in residues 807 to 867 (χ2 = 65.6, P = 1.1 × 10-17). Additionally, three CNVs involving the N-terminus of TOPORS were recorded in control populations but were absent in affected patients.
Conclusions:
This study suggests that all pathogenic truncating variants of TOPORS were clustered in residues 807 to 867, whereas the truncating variants outside this region and the CNVs involving the N-terminus were not associated with RP. A dominant-negative effect, rather than haploinsufficiency, is speculated to be the underlying pathogenesis. These findings provide valuable information for interpreting variation in TOPORS and other genes in similar situations, especially for CNVs.
... There are also other assumptions about the impact of other biological dysfunctions that affect the progressive death of photoreceptors, such as metabolic stress, inflammation [33,34]. Thus, the study of possible biological mechanisms of retinal cell degeneration remains unexplored, that requires further researches to develop effective methods of therapy for retinitis pigmentosa [35]. ...
The growing crucial problem in practical ophthalmology relates to growth of hereditary degenerative diseases of the retina, in particular retinitis, causing progressive loss of visual functions. According to international estimates, the incidence rate of hereditary dystrophy contains 1 case per 3000 population. With the development of biomedical cell technologies, transplantation of stem (autologous and allogeneic) cells is at the stage of active research.
The article reviewed literature sources on prevalence, risk factors, etiopathogenesis, diagnosis, clinical picture and treatment of retinitis pigmentosa.
... With an increased understanding of the human genome and the wide scope of genetic variants identified to be associated with IRDs (> 250 causative genes) [8], emerging genetic testing technologies such as nextgeneration sequencing are allowing clinicians to better diagnose IRDs [9][10][11]. The advent of these sophisticated testing technologies for genetic disorders has highlighted the need for broader awareness of human genetics and its relevance to personalized medicine in IRDs. ...
... Genetic testing is the analysis of an individual's DNA to detect genetic changes or variants that could lead to disease [17]. With the application of improved molecular testing technology, the likelihood of identifying a causative variant in individuals with IRDs has increased [10,11,[18][19][20]. Identifying the disease-causing variant can not only illuminate or confirm a diagnosis but can also improve medical management by informing prognosis, reducing the need for additional electrophysiologic testing, clarifying guidance in ocular surveillance, and advising appropriate changes in therapies and/or supplementation [19]. ...
Inherited retinal diseases (IRDs) are a diverse group of degenerative diseases of the retina that can lead to significant reduction in vision and blindness. Because of the considerable phenotypic overlap among IRDs, genetic testing is a critical step in obtaining a definitive diagnosis for affected individuals and enabling access to emerging gene therapy–based treatments and ongoing clinical studies. While advances in molecular diagnostic technologies have significantly improved the understanding of IRDs and identification of disease-causing variants, training in genetic diagnostics among ophthalmologists is limited. In this review, we will provide ophthalmologists with an overview of genetic testing for IRDs, including the types of available testing, variant interpretation, and genetic counseling. Additionally, we will discuss the clinical applications of genetic testing in the molecular diagnosis of IRDs through case studies.
... The proband of family PKIURP07 with Oguchi disease showed an already-reported pathogenic homozygous variant in the SAG gene NM_000541.5:c.874C>T (p.Arg292Ter) [27][28][29][30]. This mutation is a stopgain and has an allele frequency 0.000359 in gnomAD South Asia; the variant segregated with disease in both patients from this pedigree (shown in Fig. 2). ...
Aim:
Congenital stationary night blindness (CSNB) is a rare, largely non progressive, inherited retinal disorder that can be clinically classified on the basis of fundus and electroretinogram (ERG) abnormalities.
Methods:
We analyzed four large consanguineous families from the Southern Punjab region of Pakistan including multiple individuals affected with CSNB. Exome sequencing (ES) was performed in probands of all four families; Sanger sequencing was performed in additional members to test co-segregation of the variants identified.
Results:
We identified two novel and likely pathogenic variants in two pedigrees, namely NM_002905.4:c.668A>C (p.Gln223Pro) in RDH5, and NM_022567.2:c.908del (p.Gly303ValfsTer45) in NYX. In the two other families, the variants NM_002905.4:c.319G>C (p.Gly107Arg) in RDH5 and NM_000541.5:c.874C>T (p.Arg292Ter) in SAG were identified. These variants have been reported previously, but not in the Pakistani population.
Conclusions:
Our findings expand the mutational spectrum of CSNB, in particular within the population of Southern Punjab.
