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BACKGROUND: Variants in RCBTB1 were recently described to cause a retinal dystrophy with only eight families described to date and a predominant phenotype of macular atrophy and peripheral reticular degeneration. Here, we further evaluate the genotypic and phenotypic characteristics of biallelic RCBTB1-associated retinal dystrophy in a North American clinic population. METHODS: A retrospective analysis of genetic and clinical features was performed in individuals with biallelic variants in RCBTB1. RESULTS: Three unrelated individuals of French-Canadian descent with rare biallelic RCBTB1 variants were identified. All individuals shared a novel p.(Ser342Leu) missense variant; one patient was homozygous whereas the other two each possessed a second unique novel variant p.(Gln120*) and p.(Pro224Leu). All three had macular-predominant disease with symptom onset in the fifth decade of life. CONCLUSION: This report adds to the genetic diversity of RCBTB1-associated disease. These cases confirm the later-onset, relative to many other retinal dystrophies, and macular focus of disease described in most cases to-date. They are thus a reminder of considering hereditary disease in the differential for later-onset macular atrophy.

Genetic counseling services changed due to the COVID‐19 pandemic. Many genetic counselors (GCs) moved from in‐person to telehealth services. Others were redeployed by choice or necessity, using their expertise to provide COVID‐19 care and education. For some, their employment status changed due to budgetary constraints or decreasing referrals. This study surveyed North American GCs to assess the relative use of genetic counseling Practice‐Based Competencies (PBCs) as a proxy for the skills used during the first wave of the pandemic, whether GCs were in their current role or in new or adjusted roles. A secondary aim was to determine whether GCs believe their training should be refocused in view of the workforce shifts posed by the pandemic. The survey comprised closed‐ and open‐ended questions and was completed in full by 97 respondents. The study population was representative of the general genetic counseling workforce in terms of gender, race/ethnicity, age, and practice area when compared to the National Society of Genetic Counselors 2020 Professional Status Survey. Most participants (97.9%) indicated that the COVID‐19 pandemic resulted in a change to their work, and 89.7% used at least one PBC at a different frequency than before the pandemic. The most significant change was the adaptation of genetic counseling skills for varied service delivery models: 83.5% of respondents indicated that their roles and responsibilities moved to a remote setting and/or utilized telehealth. The majority of participants felt competent using the PBCs during the pandemic. Major themes that emerged from the qualitative data were as follows: (a) adaptation of service delivery, (b) translation of genetic counseling skills, and (c) provision of psychosocial support. This study highlights practice changes for GCs due to the COVID‐19 pandemic as well as the increased use of, and need for focused training in, varied service delivery models.

Pathogenic variants in INPP5E cause Joubert syndrome (JBTS), a ciliopathy with retinal involvement. However, despite sporadic cases in large cohort sequencing studies, a clear association with non-syndromic inherited retinal degenerations (IRDs) has not been made. We validate this association by reporting 16 non-syndromic IRD patients from ten families with bi-allelic mutations in INPP5E. Additional two patients showed early onset IRD with limited JBTS features. Detailed phenotypic description for all probands is presented. We report 14 rare INPP5E variants, 12 of which have not been reported in previous studies. We present tertiary protein modeling and analyze all INPP5E variants for deleteriousness and phenotypic correlation. We observe that the combined impact of INPP5E variants in JBTS and non-syndromic IRD patients does not reveal a clear genotype–phenotype correlation, suggesting the involvement of genetic modifiers. Our study cements the wide phenotypic spectrum of INPP5E disease, adding proof that sequence defects in this gene can lead to early-onset non-syndromic IRD.

PurposeIn Mendelian disease diagnosis, variant analysis is a repetitive, error-prone, and time-consuming process. To address this, we have developed the Mendelian Analysis Toolkit (MATK), a configurable automated variant ranking program.MethodsMATK aggregates variant information from multiple annotation sources and uses expert-designed rules with parameterized weights to produce a ranked list of potentially causal solutions. MATK performance was measured by a comparison of MATK-aided versus human domain-expert analyses of 1060 inherited retinal degeneration (IRD) families investigated with an IRD-specific gene panel (589 individuals) and exome sequencing (471 families).ResultsWhen comparing MATK-assisted analysis to expert curation in both IRD-specific and exome sequencing (1060 subjects), 97.3% of potential solutions found by experts were also identified by the MATK-assisted analysis (541 solutions identified with MATK of 556 solutions found by conventional analysis). Furthermore, MATK-assisted analysis identified 114 additional potential solutions from the 504 cases unsolved by the conventional analysis.ConclusionMATK expedites the process of identifying likely solving variants in Mendelian traits and reduces variability coming from human error and researcher bias. MATK facilitates data re-analysis to keep up with the constantly improving annotation sources and NGS processing pipelines. The software is open source, available at https://gitlab.com/matthew_maher/mendelanalysis

PurposePathogenic variants in INPP5E cause Joubert syndrome, a systemic disorder that can manifest with retinal degeneration among other clinical features. We aimed to evaluate the role of INPP5E variants in non-syndromic inherited retinal degenerations (IRDs) of varying severity.MethodsTargeted or genome sequencing were performed in 12 unrelated non-syndromic IRD families from multiple research hospitals. Detailed clinical examination was conducted in all probands. The impact of new likely pathogenic variants was modeled on a tertiary INPP5E protein structure and all the new and published variants were analyzed for their deleteriousness and phenotypic correlation.ResultsFourteen INPP5E rare alleles were detected, 12 of which were novel. Retinal degeneration in all 12 probands was clinically distinguishable on the basis of onset and severity into Leber congenital amaurosis (n=4) and a milder, later-onset rod-cone dystrophy (n=8). Two probands showed mild ciliopathy features that resolved in childhood. Analysis of the combined impact of both alleles in syndromic and non-syndromic INPP5E patients did not reveal clear genotype-phenotype correlation, suggesting involvement of genetic modifiers.ConclusionsThe study expands the phenotypic spectrum of disorders due to pathogenic variants in INPP5E and describes a new disease association with previously underdiagnosed forms of early-onset non-syndromic IRD.

A significant number of individuals suffer from hereditary ocular disorders and age-related vision impairments and that number is expected to double as the population ages. With the recent advancements in gene therapy shown to be effective in treating some forms of eye disease, it has become clinically relevant to provide accurate genetic diagnosis in these cases. However, considerable genetic overlap between clinical phenotypes necessitates tailored genetic testing approaches to identify the underlying causes. Furthermore, multiple classes of pathogenic variants have been associated with ocular disorders, which include coding and non-coding changes, copy number variation (CNV), and chromosomal aberrations each requiring specific sequencing strategies, while follow-up experimentation is required to fully assess their pathogenicity. This chapter discusses current methods to detect and analyze genetic variants leading to eye disease with the ultimate goal of identifying therapeutic targets for treatment.

Retinol dehydrogenase 12, RDH12, plays a pivotal role in the visual cycle to ensure the maintenance of normal vision. Alterations in activity of this protein result in photoreceptor death and decreased vision beginning at an early age and progressing to substantial vision loss later in life. Here we describe 11 patients with retinal degeneration that underwent next-generation sequencing (NGS) with a targeted panel of all currently known inherited retinal degeneration (IRD) genes and whole-exome sequencing to identify the genetic causality of their retinal disease. These patients display a range of phenotypic severity prompting clinical diagnoses of macular dystrophy, cone-rod dystrophy, retinitis pigmentosa, and early-onset severe retinal dystrophy all attributed to biallelic recessive mutations in RDH12. We report 15 causal alleles and expand the repertoire of known RDH12 mutations with four novel variants: c.215A > G (p.Asp72Gly); c.362T > C (p.Ile121Thr); c.440A > C (p.Asn147Thr); and c.697G > A (p.Val233Ille). The broad phenotypic spectrum observed with biallelic RDH12 mutations has been observed in other genetic forms of IRDs, but the diversity is particularly notable here given the prior association of RDH12 primarily with severe early-onset disease. This breadth emphasizes the importance of broad genetic testing for inherited retinal disorders and extends the pool of individuals who may benefit from imminent gene-targeted therapies.