WDR34, a candidate gene for non-syndromic rod-cone dystrophy

Rod-cone dystrophy (RCD), also called retinitis pigmentosa, is characterized by rod followed by cone photoreceptor degeneration, leading to gradual visual loss. Mutations in over 65 genes have been associated with non-syndromic RCD explaining 60% to 70% of cases, with novel gene defects possibly accounting for the unsolved cases. Homozygosity mapping and whole-exome sequencing applied to a case of autosomal recessive non-syndromic RCD from a consanguineous union identified a homozygous variant in WDR34. Mutations in WDR34 have been previously associated with severe ciliopathy syndromes possibly associated with a retinal dystrophy. This is the first report of a homozygous mutation in WDR34 associated with non-syndromic RCD.Doctoral funding from the Ministère de l'Enseignement Supérieur et de la Recherche; Europe exchange 2018 Erasmus; European Reintegration Grant, Grant/Award Number: PERG04-GA-2008-231125; Fondation de France-Berthe Fouassier; Foundation Fighting Blindness, Grant/Award Number: Grant # CD-CL-0808-0466-CHNO CIC503 recogn; Foundation Voir et Entendre; French Agence Nationale de la Recherche, Grant/Award Numbers: IHU FOReSIGHT: ANR-18-IAHU-0001, LIFESENSES: ANR-10-LABX-65; National Eye Institute [R01EY012910 (EAP), R01EY026904 (KMB/EAP) and P30EY014104 (MEEI core support)], the Foundation Fightin

High prevalence of PRPH2 in autosomal dominant retinitis pigmentosa in France and characterization of biochemical and clinical features.

International audiencePURPOSE:To assess the prevalence of PRPH2 in autosomal dominant retinitis pigmentosa (adRP), to report six novel mutations, to characterize the biochemical features of a recurrent novel mutation and to study the clinical features of adRP patients.DESIGN:Retrospective clinical and molecular genetic study.METHODS:Clinical investigations included visual field testing, fundus examination, high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence imaging and electroretinogram (ERG) recording. PRPH2 was screened by Sanger sequencing in a cohort of 310 French families with adRP. Peripherin-2 protein was produced in yeast and analyzed by Western blot.RESULTS:We identified 15 mutations, including 6 novel and 9 previously reported changes in 32 families, accounting for a prevalence of 10.3% in this adRP population. We showed that a new recurrent p.Leu254Gln mutation leads to protein aggregation, suggesting abnormal folding. The clinical severity of the disease in examined patients was moderate with 78% of the eyes having 1 to 0.5 of visual acuity and 52% of the eyes retaining more than 50% of the visual field. Some patients characteristically showed vitelliform deposits or macular involvement. In some families, pericentral RP or macular dystrophy were found in family members while widespread RP was present in other members of the same families.CONCLUSIONS:The mutations in PRPH2 account for 10.3% of adRP in the French population, which is higher than previously reported (0-8%) This makes PRPH2 the second most frequent adRP gene after RHO in our series. PRPH2 mutations cause highly variable phenotypes and moderate forms of adRP, including mild cases which could be underdiagnosed

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Using cluster analysis to identify patterns in students’ responses to contextually different conceptual problems

This study examined the evolution of student responses to seven contextually different versions of two Force Concept Inventory questions in an introductory physics course at the University of Arkansas. The consistency in answering the closely related questions evolved little over the seven-question exam. A model for the state of student knowledge involving the probability of selecting one of the multiple-choice answers was developed. Criteria for using clustering algorithms to extract model parameters were explored and it was found that the overlap between the probability distributions of the model vectors was an important parameter in characterizing the cluster models. The course data were then clustered and the extracted model showed that students largely fit into two groups both pre- and postinstruction: one that answered all questions correctly with high probability and one that selected the distracter representing the same misconception with high probability. For the course studied, 14% of the students were left with persistent misconceptions post instruction on a static force problem and 30% on a dynamic Newton’s third law problem. These students selected the answer representing the predominant misconception slightly more consistently postinstruction, indicating that the course studied had been ineffective at moving this subgroup of students nearer a Newtonian force concept and had instead moved them slightly farther away from a correct conceptual understanding of these two problems. The consistency in answering pairs of problems with varied physical contexts is shown to be an important supplementary statistic to the score on the problems and suggests that the inclusion of such problem pairs in future conceptual inventories would be efficacious. Multiple, contextually varied questions further probe the structure of students’ knowledge. To allow working instructors to make use of the additional insight gained from cluster analysis, it is our hope that the physics education research community will make these methods available though their Web sites

A novel DFNB31 mutation associated with Usher type 2 syndrome showing variable degrees of auditory loss in a consanguineous Portuguese family

Purpose: To identify the genetic defect of a consanguineous Portuguese family with rod-cone dystrophy and varying degrees of decreased audition. Methods: A detailed ophthalmic and auditory examination was performed on a Portuguese patient with severe autosomal recessive rod-cone dystrophy. Known genetic defects were excluded by performing autosomal recessive retinitis pigmentosa (arRP) genotyping microarray analysis and by Sanger sequencing of the coding exons and flanking intronic regions of eyes shut homolog-drosophila (EYS) and chromosome 2 open reading frame 71 (C2orf71). Subsequently, genome-wide homozygosity mapping was performed in DNA samples from available family members using a 700K single nucleotide polymorphism (SNP) microarray. Candidate genes present in the significantly large homozygous regions were screened for mutations using Sanger sequencing. Results: The largest homozygous region (~11 Mb) in the affected family members was mapped to chromosome 9, which harbors deafness, autosomal recessive 31 (DFNB31; a gene previously associated with Usher syndrome). Mutation analysis of DFNB31 in the index patient identified a novel one-base-pair deletion (c.737delC), which is predicted to lead to a truncated protein (p.Pro246HisfsX13) and co-segregated with the disease in the family. Ophthalmic examination of the index patient and the affected siblings showed severe rod-cone dystrophy. Pure tone audiometry revealed a moderate hearing loss in the index patient, whereas the affected siblings were reported with more profound and early onset hearing impairment. Conclusions: We report a novel truncating mutation in DFNB31 associated with severe rod-cone dystrophy and varying degrees of hearing impairment in a consanguineous family of Portuguese origin. This is the second report of DFNB31 implication in Usher type 2. © 2011 Molecular Vision.The project was financially supported by the Foundation Fighting Blindness (I.A. FFB Grant N°: CD-CL-0808–0466-CHNO and the CIC503 recognized as an FFB center, FFB Grant No: C-CMM-0907–0428-INSERM04), Agence Nationale de la Recherche (S.S.B.), Foundation Voir et Entendre (C.Z.), Ville de Paris and region Ile de France.Peer Reviewe

The Cenomanian lignitic clays of Hucheloup(Écouflant, Maine-et-Loire) : palaeobotanicaland palaeoenvironmental study

National audienceThe Anjou region is located in the western part of the ParisBasin at the south-east of the Armorican Massif. The Cenomanianclays of Le Brouillard quarry (near Ecouflant, Maine-et-Loire) yielded exceptionally preserved plant macroremains. Theyincluded centimetric compressions of Conifers, Ginkgoales, andAngiosperms. This quarry was studied during the second half ofthe 20th century but was partially filled in 2005, rendering furtherstudies impossible. However, in 2006, new fossiliferous depositswere discovered in the Hucheloup quarry, located one kilometerwest of Le Brouillard. The Hucheloup quarry displays a successionof sand and clay, presumably Cenomanian in age. Clays yielda diverse fossil assemblage which was already, partly, studied byNéraudeau et al. (2013) and Durand (2014). It is dominatedby coastal marine and brackish bivalves, mostly of the generaBrachidontes (fam. Mytilidae) and Protocardia (fam. Cardiidae),and contains an important diversity of plant impressionsand compressions, mainly preserved as fragmented leaf remains,with or without cuticle. The plants have been transported, onlythe brackish bivalves seem to be autochtonous. Plants wereascribed to diverse Pinales (29%), Pteridophytes (29%), Ginkgoales(24%), Angiosperms (17%) and Cycads (1%). The mostabundant species are Frenelopsis alata (Pinales) and Eretmophyllumandegavense (Ginkgoales). The co-occurence of those twospecies is frequently found in Europe in estuarine mid-Cretaceousdeposits. The fauna also includes arthropod remains such as insecteggs and a fragmented carapace of Meyeria sp. (Crustacean),as well as bryozoans and brachiopods. The taphonomical, sedimentological,and palaeoecological data revealed that the fossilremains were deposited in a brackish lagoon or the lower partof what was likely an estuary. It allowed the preservation of arich biodiversity that developed under a tropical climate, at theocean/land transition

A novel DFNB31 mutation associated with Usher type 2 syndrome showing variable degrees of auditory loss in a consanguineous Portuguese family.

International audiencePURPOSE:To identify the genetic defect of a consanguineous Portuguese family with rod-cone dystrophy and varying degrees of decreased audition.METHODS:A detailed ophthalmic and auditory examination was performed on a Portuguese patient with severe autosomal recessive rod-cone dystrophy. Known genetic defects were excluded by performing autosomal recessive retinitis pigmentosa (arRP) genotyping microarray analysis and by Sanger sequencing of the coding exons and flanking intronic regions of eyes shut homolog-drosophila (EYS) and chromosome 2 open reading frame 71 (C2orf71). Subsequently, genome-wide homozygosity mapping was performed in DNA samples from available family members using a 700K single nucleotide polymorphism (SNP) microarray. Candidate genes present in the significantly large homozygous regions were screened for mutations using Sanger sequencing.RESULTS:The largest homozygous region (~11 Mb) in the affected family members was mapped to chromosome 9, which harbors deafness, autosomal recessive 31 (DFNB31; a gene previously associated with Usher syndrome). Mutation analysis of DFNB31 in the index patient identified a novel one-base-pair deletion (c.737delC), which is predicted to lead to a truncated protein (p.Pro246HisfsX13) and co-segregated with the disease in the family. Ophthalmic examination of the index patient and the affected siblings showed severe rod-cone dystrophy. Pure tone audiometry revealed a moderate hearing loss in the index patient, whereas the affected siblings were reported with more profound and early onset hearing impairment.CONCLUSIONS:We report a novel truncating mutation in DFNB31 associated with severe rod-cone dystrophy and varying degrees of hearing impairment in a consanguineous family of Portuguese origin. This is the second report of DFNB31 implication in Usher type 2

Development of Novel Patient-Reported Outcome (PRO) and Observer-Reported Outcome (ObsRO) Instruments in Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA): ViSIO-PRO and ViSIO-ObsRO

Abstract Introduction Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are rare inherited retinal degenerative disorders resulting in visual impairments and impacts on patients’ vision-dependent activities of daily living (ADL), mobility and distal health-related quality of life (HRQoL). This study aimed to conduct qualitative research to understand the patient experience of RP/LCA across genotypes and inform development of patient- and observer-reported outcome (PRO/ObsRO) instruments in RP/LCA. Methods Research activities included a qualitative literature review and review of existing visual function PRO instruments in RLBP1 RP, and concept elicitation (CE) and cognitive debriefing (CD) interviews of existing PRO instruments with patients with RLBP1 RP, expert clinicians, and payers. In wider RP/LCA, a social media listening (SML) study and a qualitative literature review was conducted, while psychometric evaluation of a PRO instrument in LCA was performed. Input from expert clinicians was sought at key stages. Results Findings from the qualitative literature reviews identified a range of visual function symptoms which had significant impacts on patients’ vision-related ADL and distal HRQoL. Patient interviews identified additional visual function symptoms and impacts not previously reported in published literature. These sources informed development and refinement of a conceptual model displaying the patient experience of RP/LCA. Review of existing visual function PRO instruments, and CD interviews evaluating their content validity, confirmed that no existing instrument provides a comprehensive assessment of all concepts relevant to patients with RP/LCA. This highlighted the need for development of the Visual Symptom and Impact Outcomes PRO and ObsRO instruments to adequately assess the patient experience of RP/LCA. Conclusions Results informed and supported development of the instruments to assess visual functioning symptoms and vision-dependent ADL, mobility and distal HRQoL in RP/LCA, in accordance with regulatory standards. Next steps to further support use in RP/LCA clinical trials/practice includes content and psychometric validation of the instruments in this population