A qualitative study among patients with an inherited retinal disease on the meaning of genomic unsolicited findings.
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ABSTRACT:
SUBMITTER: Saelaert M
PROVIDER: S-EPMC8339116 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Unsolicited findings (UFs) in clinical exome sequencing are variants that are unrelated to the initial clinical question the DNA test was performed for, but that may nonetheless be of medical relevance to patients and/or their families. There is limited knowledge about the impact of UFs on patients' lives. In order to characterise patient perceptions of the impact of an UF, we conducted 20 semi-structured face-to-face interviews with patients and/or their relatives to whom an UF predisposing to oncological disease (n = 10) or predisposing to a cardiac condition (n = 10) had been disclosed. We have identified a psychological, physical and financial aspect of the perceived impact of UF disclosure in exome sequencing. Actionability, understanding, patients' pre-test health and social context were influencing factors, according to our participants. Although most expressed considerable psychological impact initially, all but one participant would choose to undergo genetic testing again, knowing what they know now. These novel findings provide insight in patients' perspectives on the impact of UF disclosure. Our study highlights the value of incorporating patients' perceptions in UF disclosure policy.
| S-EPMC8187681 | biostudies-literature
Project description:BACKGROUND:Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous set of disorders, for which diagnostic second-generation sequencing (next-generation sequencing, NGS) services have been developed worldwide. METHODS:We present the molecular findings of 537 individuals referred to a 105-gene diagnostic NGS test for IRDs. We assess the diagnostic yield, the spectrum of clinical referrals, the variant analysis burden and the genetic heterogeneity of IRD. We retrospectively analyse disease-causing variants, including an assessment of variant frequency in Exome Aggregation Consortium (ExAC). RESULTS:Individuals were referred from 10 clinically distinct classifications of IRD. Of the 4542 variants clinically analysed, we have reported 402 mutations as a cause or a potential cause of disease in 62 of the 105 genes surveyed. These variants account or likely account for the clinical diagnosis of IRD in 51% of the 537 referred individuals. 144 potentially disease-causing mutations were identified as novel at the time of clinical analysis, and we further demonstrate the segregation of known disease-causing variants among individuals with IRD. We show that clinically analysed variants indicated as rare in dbSNP and the Exome Variant Server remain rare in ExAC, and that genes discovered as a cause of IRD in the post-NGS era are rare causes of IRD in a population of clinically surveyed individuals. CONCLUSIONS:Our findings illustrate the continued powerful utility of custom-gene panel diagnostic NGS tests for IRD in the clinic, but suggest clear future avenues for increasing diagnostic yields.
| S-EPMC5106339 | biostudies-literature
Project description:PURPOSE:Secondary findings from genomic sequencing are becoming more common. We compared how health-care providers with and without specialized genetics training anticipated responding to different types of secondary findings. METHODS:Providers with genomic sequencing experience reviewed five secondary-findings reports and reported attitudes and potential clinical follow-up. Analyses compared genetic specialists and physicians without specialized genetics training, and examined how responses varied by secondary finding. RESULTS:Genetic specialists scored higher than other providers on four-point scales assessing understandings of reports (3.89 vs. 3.42, p?=?0.0002), and lower on scales assessing reporting obligations (2.60 vs. 3.51, p?<?0.0001) and burdens of responding (1.73 vs. 2.70, p?<?0.0001). Nearly all attitudes differed between findings, although genetic specialists were more likely to assert that laboratories had no obligations when findings had less-established actionability (p?<?0.0001 in interaction tests). The importance of reviewing personal and family histories, documenting findings, learning more about the variant, and recommending familial discussions also varied according to finding (all p?<?0.0001). CONCLUSION:Genetic specialists felt better prepared to respond to secondary findings than providers without specialized genetics training, but perceived fewer obligations for laboratories to report them, and the two groups anticipated similar clinical responses. Findings may inform development of targeted education and support.
| S-EPMC6103906 | biostudies-literature
Project description:The Irish national registry for inherited retinal degenerations (Target 5000) is a clinical and scientific program to identify individuals in Ireland with inherited retinal disorders and to attempt to ascertain the genetic cause underlying the disease pathology. Potential participants first undergo a clinical assessment, which includes clinical history and analysis with multimodal retinal imaging, electrophysiology, and visual field testing. If suitable for recruitment, a sample is taken and used for genetic analysis. Genetic analysis is conducted by use of a retinal gene panel target capture sequencing approach. With over 1000 participants from 710 pedigrees now screened, there is a positive candidate variant detection rate of approximately 70% (495/710). Where an autosomal recessive inheritance pattern is observed, an additional 9% (64/710) of probands have tested positive for a single candidate variant. Many novel variants have also been detected as part of this endeavor. The target capture approach is an economic and effective means of screening patients with inherited retinal disorders. Despite the advances in sequencing technology and the ever-decreasing associated processing costs, target capture remains an attractive option as the data produced is easily processed, analyzed, and stored compared to more comprehensive methods. However, with decreasing costs of whole genome and whole exome sequencing, the focus will likely move towards these methods for more comprehensive data generation.
| S-EPMC7016747 | biostudies-literature
Project description:PURPOSE:Physicians increasingly receive genomic test results they did not order, which we term "unsolicited genomic results" (UGRs). We asked physicians how they think such results will affect them and their patients. METHODS:Semistructured interviews were conducted with adult and pediatric primary care and subspecialty physicians at four sites affiliated with a large-scale return-of-results project led by the Electronic Medical Records and Genomics (eMERGE) Network. Twenty-five physicians addressed UGRs and (1) perceived need for actionability, (2) impact on patients, (3) health care workflow, (4) return of results process, and (5) responsibility for results. RESULTS:Physicians prioritize actionability of UGRs and the need for clear, evidence-based "paths" for action coupled with clinical decision support (CDS). They identified potential harms to patients including anxiety, false reassurance, and clinical disutility. Clinicians worried about anticipated workflow issues including responding to UGRs and unreimbursed time. They disagreed about who was responsible for responding to UGRs. CONCLUSION:The prospect of receiving UGRs for otherwise healthy patients raises important concerns for physicians. Their responses informed development of an in-depth survey for physicians following return of UGRs. Strategic workflow integration of UGRs will likely be necessary to empower physicians to serve their patients effectively.
| S-EPMC6294706 | biostudies-literature
Project description:Inherited retinal degenerations are a common cause of untreatable blindness worldwide, with retinitis pigmentosa and cone dystrophy affecting approximately 1 in 3500 and 1 in 10,000 individuals, respectively. A major limitation to the development of effective therapies is the lack of availability of animal models that fully replicate the human condition. Particularly for cone disorders, rodent, canine, and feline models with no true macula have substantive limitations. By contrast, the cone-rich macula of a nonhuman primate (NHP) closely mirrors that of the human retina. Consequently, well-defined NHP models of heritable retinal diseases, particularly cone disorders that are predictive of human conditions, are necessary to more efficiently advance new therapies for patients. We have identified 4 related NHPs at the California National Primate Research Center with visual impairment and findings from clinical ophthalmic examination, advanced retinal imaging, and electrophysiology consistent with achromatopsia. Genetic sequencing confirmed a homozygous R565Q missense mutation in the catalytic domain of PDE6C, a cone-specific phototransduction enzyme associated with achromatopsia in humans. Biochemical studies demonstrate that the mutant mRNA is translated into a stable protein that displays normal cellular localization but is unable to hydrolyze cyclic GMP (cGMP). This NHP model of a cone disorder will not only serve as a therapeutic testing ground for achromatopsia gene replacement, but also for optimization of gene editing in the macula and of cone cell replacement in general.
| S-EPMC6355306 | biostudies-literature
Project description:This paper investigates the willingness of adults with inherited retinal disease to undergo and pay for diagnostic genetic testing in three hypothetical scenarios and to explore the factors that influence decision making. Fifty patients were presented with three scenarios whereby genetic testing provided increasing information: confirming the diagnosis and inheritance pattern alone, providing additional information on future visual function, and identifying in addition a new treatment which could stabilise their condition. Willingness to pay (WTP) was elicited using an iterative bidding game. Regression analysis was used to investigate the probability of agreeing to and paying for testing. Qualitative data were also reviewed to provide a comprehensive understanding of WTP and decision making. The majority of participants agreed to undergo genetic testing in each of the three scenarios. Scenario 2 was the least acceptable with 78% of participants agreeing to genetic testing. The probability of agreeing to genetic testing decreased with age. Between 72 and 96% of participants reported a WTP for genetic testing. Average WTP was £539, £1516, and £6895 for scenarios 1, 2, and 3 respectively. Older participants and participants with higher incomes were willing to pay more for testing. Qualitative data provided additional detail about the rationale behind participants' decisions. The study suggests that patients with inherited retinal disease were willing to undergo and to pay for diagnostic genetic testing, suggesting that they valued the information it may provide. However, several patients preferred not to receive prognostic information and were less willing to pay for genetic testing that yielded such detail.
| S-EPMC4326707 | biostudies-other
Project description:Inherited retinal diseases (IRDs) are a group of rare, heterogenous eye disorders caused by gene mutations that result in degeneration of the retina. There are currently limited treatment options for IRDs; however, retinal gene therapy holds great promise for the treatment of different forms of inherited blindness. One such IRD for which gene therapy has shown positive initial results is choroideremia, a rare, X-linked degenerative disorder of the retina and choroid. Mutation of the CHM gene leads to an absence of functional Rab escort protein 1 (REP1), which causes retinal pigment epithelium cell death and photoreceptor degeneration. The condition presents in childhood as night blindness, followed by progressive constriction of visual fields, generally leading to vision loss in early adulthood and total blindness thereafter. A recently developed adeno-associated virus-2 (AAV2) vector construct encoding REP1 (AAV2-REP1) has been shown to deliver a functional version of the CHM gene into the retinal pigment epithelium and photoreceptor cells. Phase 1 and 2 studies of AAV2-REP1 in patients with choroideremia have produced encouraging results, suggesting that it is possible not only to slow or stop the decline in vision following treatment with AAV2-REP1, but also to improve visual acuity in some patients.
| S-EPMC6534121 | biostudies-literature
Project description:BACKGROUND: Visual dysfunction is common in Parkinson's disease (PD). It remains, however, unknown whether it is related to structural alterations of the retina. The aim of this study is to compare visual field (VF) findings and circumpapillary retinal nerve fiber layer (RNFL) thickness in a series of PD patients and normal controls, in order to assess possible retinal anatomical changes and/or functional damage associated with PD. METHODS: PD patients and controls were recruited and underwent VF testing with static automated perimetry and RNFL examination with optical coherence tomography (OCT). Cognitive performance using Mini Mental State Examination (MMSE), PD staging using modified Hoehn and Yahr (H-Y) scale and duration of the disease was recorded in PD patients. RESULTS: One randomly selected eye from each of 24 patients and 24 age-matched controls was included. OCT RNFL thickness analysis revealed no difference in the inferior, superior, nasal or temporal sectors between the groups. The average peripapillary RNFL was also similar in the two groups. However, perimetric indices of generalized sensitivity loss (mean deviation) and localized scotomas (pattern standard deviation) were worse in patients with PD compared to controls (p?<?0.01). 73% of eyes of PD patients had glaucomatous-like asymmetrical hemifield defects with abnormal Glaucoma Hemifield Test and various combinations of arcuate defects (n?=?12), nasal steps (n?=?11) and paracentral scotomas (n?=?16). Bilateral defects were found in 14 patients (58%). No correlation was found between VF indices and MMSE or H-Y scores. CONCLUSION: PD patients may demonstrate glaucomatous-like perimetric defects even in the absence of decreased RNFL thickness.
| S-EPMC3515471 | biostudies-literature
Project description:Inherited retinal diseases (IRD) are a leading cause of blindness in the working age population. The advances in ocular genetics, retinal imaging and molecular biology, have conspired to create the ideal environment for establishing treatments for IRD, with the first approved gene therapy and the commencement of multiple therapy trials. The scope of this review is to familiarize clinicians and scientists with the current landscape of retinal imaging in IRD. Herein we present in a comprehensive and concise manner the imaging findings of: (I) macular dystrophies (MD) [Stargardt disease (ABCA4), X-linked retinoschisis (RS1), Best disease (BEST1), pattern dystrophy (PRPH2), Sorsby fundus dystrophy (TIMP3), and autosomal dominant drusen (EFEMP1)], (II) cone and cone-rod dystrophies (GUCA1A, PRPH2, ABCA4 and RPGR), (III) cone dysfunction syndromes [achromatopsia (CNGA3, CNGB3, PDE6C, PDE6H, GNAT2, ATF6], blue-cone monochromatism (OPN1LW/OPN1MW array), oligocone trichromacy, bradyopsia (RGS9/R9AP) and Bornholm eye disease (OPN1LW/OPN1MW), (IV) Leber congenital amaurosis (GUCY2D, CEP290, CRB1, RDH12, RPE65, TULP1, AIPL1 and NMNAT1), (V) rod-cone dystrophies [retinitis pigmentosa, enhanced S-Cone syndrome (NR2E3), Bietti crystalline corneoretinal dystrophy (CYP4V2)], (VI) rod dysfunction syndromes (congenital stationary night blindness, fundus albipunctatus (RDH5), Oguchi disease (SAG, GRK1), and (VII) chorioretinal dystrophies [choroideremia (CHM), gyrate atrophy (OAT)].
| S-EPMC8081382 | biostudies-literature