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Biallelic STX3 variants were previously reported in five individuals with the severe congenital enteropathy, microvillus inclusion disease (MVID). Here, we provide a significant extension of the phenotypic spectrum caused by STX3 variants. We report ten individuals of diverse geographic origin with biallelic STX3 loss-of-function variants, identified through exome sequencing, single-nucleotide polymorphism array-based homozygosity mapping, and international collaboration. The evaluated individuals all presented with MVID. Eight individuals also displayed early-onset severe retinal dystrophy, i.e., syndromic—intestinal and retinal—disease. These individuals harbored STX3 variants that affected both the retinal and intestinal STX3 transcripts, whereas STX3 variants affected only the intestinal transcript in individuals with solitary MVID. That STX3 is essential for retinal photoreceptor survival was confirmed by the creation of a rod photoreceptor-specific STX3 knockout mouse model which revealed a time-dependent reduction in the number of rod photoreceptors, thinning of the outer nuclear layer, and the eventual loss of both rod and cone photoreceptors. Together, our results provide a link between STX3 loss-of-function variants and a human retinal dystrophy. Depending on the genomic site of a human loss-of-function STX3 variant, it can cause MVID, the novel intestinal-retinal syndrome reported here or, hypothetically, an isolated retinal dystrophy.

ZusammenfassungDie augenärztliche Begutachtung unterscheidet sich in den verschiedenen Rechtsgebieten deutlich, so gelten unterschiedliche Kausalitäten und Beweismaßstäbe, und die Bewertung muss unterschiedlichen Maßstäben folgen. Für die 3 wichtigen Teilbereiche der Privaten und der Gesetzlichen Unfallversicherung sowie dem Schwerbehindertenrecht bzw. dem sozialen Entschädigungsrecht existieren abstrakte tabellarische Vorgaben. Die Grundlagen der Begutachtung in diesen Rechtsgebieten werden vergleichend dargestellt, dabei wird besonders auf die Kausalität eingegangen.

ZusammenfassungDas Bardet-Biedl-Syndrom (BBS) ist eine seltene, erblich bedingte Ziliopathie, bei der neben einer Netzhautdystrophie, meist in Form einer Stäbchen-Zapfen-Dystrophie (Retinitis pigmentosa, RP), zahlreiche weitere Symptome bestehen, vor allem Stammfettsucht, Polydaktylie, Nierenveränderungen und Lernbehinderung bzw. Intelligenzminderung. Mindestens 25 ursächliche Gene, die für Proteine mit wichtiger Rolle bei Entwicklung und Funktion primärer Zilien kodieren, sind bisher bekannt. Die Störung der mit zahlreichen Entwicklungssignalwegen assoziierten Zilien erklärt die in unterschiedlichen Organen auftretenden Symptome. Aufgrund der ursächlichen Beteiligung so vieler Gene ist das BBS eine Erkrankung, bei der Ärzte in besonderem Maße von neuen Methoden der molekulargenetischen Diagnostik profitieren: Durch Next-Generation Sequencing (NGS) können alle krankheitsrelevanten Gene im Rahmen einer sogenannten „Panelanalyse“ parallel untersucht werden. Signifikante Genotyp-Phänotyp-Korrelationen hinsichtlich der Art der Netzhautbeteiligung bestehen nicht. Neben der klassischen autosomal-rezessiven Vererbung wurden oligogene oder triallelische Vererbungsformen, bei denen die Erkrankung aus einem kombinierten Effekt verschiedener Allele in mehreren Genen resultiert, beschrieben. Nach heutigem Kenntnisstand, der zunehmend aus großen NGS-Studien gespeist wird, spielen Letztere aber keine (wesentliche) Rolle. Mangels kausaler Therapieansätze beschränkt sich die augenärztliche Behandlung auf eine umfassende Rehabilitation mit vergrößernden Sehhilfen sowie die Versorgung mit Langstock und dem Training von lebenspraktischen Fähigkeiten.

Glaucoma and pregnancy is an uncommon combination, but it constitutes a very challenging situation for the treating doctor. The challenge is not only controlling the intraocular pressure and preventing glaucoma progression in the mother, but also having to deal with her mental stress and anxiety regarding the safety of her child. The situation is further worsened by the lack of definite guidelines as to how to deal with such patients. Relative rarity of glaucoma in this population restricts any large prospective randomized clinical trials or any large systematic studies. Moreover, none of the existing anti-glaucoma medications is absolutely safe in pregnancy. Current practice patterns depend on some case reports, a few observational studies and a few animal studies that attempt at determining the safety and efficacy of the available medicines. These are then prescribed on the basis of their relative safety in any particular stage of pregnancy or lactation. Newer medications that were released recently in 2018, such as Vyzulta and Rhopressa, presently have limited data to support their safety for use during pregnancy. Laser trabeculoplasty, conventional filtration surgery (of course without anti-metabolites), and minimally invasive glaucoma surgery represent a few non-pharmacological management options. Surgical procedures such as trabeculectomy and tube-shunts or collagen matrix implants, and newer minimally invasive glaucoma surgery procedures such as the gelatin stents are currently being explored and may prove to be viable solutions for severe glaucoma during pregnancy, although they too have their own inherent drawbacks. Management of glaucoma during pregnancy and lactation requires careful consideration of the disease status, gestational stage, US Food and Drug Administration classification and guidelines, and potential benefits and limitations of the various therapeutic modalities. This review focuses on the importance of a multidisciplinary team approach, starting with preconception planning and counseling, determining the treatment options depending on the stage of glaucoma and of pregnancy, and emphasizes the involvement of the patients, their obstetrician, and pediatrician through active discussion regarding the various medical, laser, or surgical modalities currently available or under exploration for use during pregnancy and lactation. The ultimate aim is to achieve an optimal balance between the risks and benefits of any type of intervention, and to customize treatment on an individual basis in order to achieve the best outcomes for both mother and fetus.

Die Bestimmung der Sehscharfe besonders zu gutachtlichen Zwecken erfolgt mit Landolt-Ringen. In der klinischen Praxis ist eine solche Sehscharfeprufung aus verschiedenen Grunden schlecht praktizierbar und nicht ublich. Wir untersuchten deshalb, wie sich der Visus bei Prufung mit Landolt-Ringen gegenuber dem Visus mit Zahlen unterscheidet. Es erfolgte eine retrospektive Auswertung der Sehscharfeprufung an 2335 Augen von 1394 Patienten (Alter 5 bis 98 Jahre, Median 51 Jahre) der Sehbehindertenambulanz der Univ.-Augenklinik Heidelberg. Die Patienten hatten unterschiedlichste Augenerkrankungen. Bei allen erfolgte die Sehscharfeprufung fur Zahlen und Landolt-Ringe in identischer Weise DIN-gerecht. Die Sehscharfe wurde als LogMAR angegeben und intraindividuell verglichen. Zwischen den Ergebnissen mit beiden Optotypen bestand zwar eine hohe Korrelation von r2 = 0,927, doch im Mittel unterschieden sich die Sehscharfen deutlich mit 0,13 ± 0,14 LogMAR. Mit Zahlen wurde eine um 0,13 LogMAR hohere Sehscharfe ermittelt, etwas mehr als 1 Zeile. Diese Unterschiede waren weitgehend unabhangig von der Sehscharfe und nahmen mit dem Alter etwas zu. Die Schwankungen waren allerdings fur geringe Sehscharfen groser. Wahrend die Sehscharfe im klinischen Alltag typischerweise mit Zahlen gepruft wird und wissenschaftlich meist ETDRS-Tafeln zum Einsatz kommen, erlaubt lediglich die Benutzung von Landolt-Ringen eine Untersuchung ohne Einfluss der Formerkennung. Diese sind daher fur rechtliche Belange in Europa nach der EN ISO 8596 bzw. in Deutschland nach DIN 58220 gultig. Die Ergebnisse bestatigen fruhere Arbeiten zum Vergleich mit E‑Haken oder Lea-Symbolen dahingehend, dass Landolt-Ringe in einer geringeren Sehscharfe resultieren. Im Mittel ist der Visus um etwa 1 Zeile schlechter als mit Zahlen. Dies spricht fur einen nicht korrekten Anschluss der Zahlen des Polatests mit einer Abweichung von mehr als den erlaubten 0,05 LogMAR. Es ist daher fur eine gutachtliche Beurteilung wichtig, den Visus korrekt mit Landolt-Ringen zu erheben.

The ophthalmological appraisal differs significantly in the different areas of law, so there are some different causalities and standards of proof and, above all, the assessment is very different. For the three important sub-areas of private accident insurance, statutory accident insurance as well as disability law and social compensation law, there are abstract tabular guidelines which form the essential basis for a comparable and thus fair assessment. The basics of the assessment in these fields of law are presented in a comparative way, with particular emphasis on causality.

The Bardet-Biedl syndrome (BBS) is a rare inherited ciliopathy, which is accompanied by retinal disease, i.e. rod-cone dystrophy (retinitis pigmentosa, RP) and other symptoms, especially truncal obesity, polydactyly, renal abnormalities as well as reduced intelligence or learning difficulties. 25 BBS genes are currently known, and these are responsible for the structure and function of primary cilia. Because ciliary integrity is crucial for numerous pathways of developmental signaling, their dysfunction may cause multisystemic disorders - like BBS. Physicians benefit greatly from new molecular genetic methods that have made genetically heterogeneous conditions diagnostically accessible: By next-generation sequencing (NGS), all BBS-associated genes can be analysed simultaneously in a gene panel. As regards the retinal phenotype, genotype-phenotype correlations are not significant. Besides classical autosomal recessive inheritance, oligogenic/triallelic traits have been reported, but these seem to play a minor role, if any (as a growing number of large-scale NGS-based studies suggests). In the absence of causal therapy, the mainstay of ophthalmological endeavour is focused on visual rehabilitation with low vision aids, use of the white cane and training to develop everyday life skills.Das Bardet-Biedl-Syndrom (BBS) ist eine seltene, erblich bedingte Ziliopathie, bei der neben einer Netzhautdystrophie, meist in Form einer Stäbchen-Zapfen-Dystrophie (Retinitis pigmentosa, RP), zahlreiche weitere Symptome bestehen, vor allem Stammfettsucht, Polydaktylie, Nierenveränderungen und Lernbehinderung bzw. Intelligenzminderung. Mindestens 25 ursächliche Gene, die für Proteine mit wichtiger Rolle bei Entwicklung und Funktion primärer Zilien kodieren, sind bisher bekannt. Die Störung der mit zahlreichen Entwicklungssignalwegen assoziierten Zilien erklärt die in unterschiedlichen Organen auftretenden Symptome. Aufgrund der ursächlichen Beteiligung so vieler Gene ist das BBS eine Erkrankung, bei der Ärzte in besonderem Maße von neuen Methoden der molekulargenetischen Diagnostik profitieren: Durch Next-Generation Sequencing (NGS) können alle krankheitsrelevanten Gene im Rahmen einer sogenannten „Panelanalyse“ parallel untersucht werden. Signifikante Genotyp-Phänotyp-Korrelationen hinsichtlich der Art der Netzhautbeteiligung bestehen nicht. Neben der klassischen autosomal-rezessiven Vererbung wurden oligogene oder triallelische Vererbungsformen, bei denen die Erkrankung aus einem kombinierten Effekt verschiedener Allele in mehreren Genen resultiert, beschrieben. Nach heutigem Kenntnisstand, der zunehmend aus großen NGS-Studien gespeist wird, spielen Letztere aber keine (wesentliche) Rolle. Mangels kausaler Therapieansätze beschränkt sich die augenärztliche Behandlung auf eine umfassende Rehabilitation mit vergrößernden Sehhilfen sowie die Versorgung mit Langstock und dem Training von lebenspraktischen Fähigkeiten.

Light filters with wavelength-dependent transmission and in particular cut-off or step filters (steep dependence of transmission on wavelength) have a broad optical application and are relevant in ophthalmology. This article describes some physical and physiological principles of cut-off filters, discusses the physiological aspects of applications, specifically the not always relevant necessity of blue-reducing filters and the lack of efficacy of color filters with color vision deficiencies.

ZusammenfassungDie Anforderungen an das Sehvermögen zur Fahreignung sind in Anlage 6 zur Fahrerlaubnisverordnung festgelegt. Bei Störungen ist in der Regel eine augenärztliche Beurteilung erforderlich. Der begutachtende Augenarzt sollte es als seine primäre Aufgabe ansehen, bei der Beurteilung der Fahrerlaubnis alle augenärztlichen Möglichkeiten auszuschöpfen, den Bewerber um eine Fahrerlaubnis tauglich zu machen oder zu halten. In der überwiegenden Mehrzahl der Fälle gelingt dies auch.Allerdings ist es unvermeidlich, bei plötzlichem schwerwiegendem einseitigem Sehverlust für 3 Monate ab dem Auftreten die gesetzlich vorgeschriebene Fahruntauglichkeit zu attestieren. Bei Motilitätsstörungen entscheiden vor allem die Ausdehnung der Doppelbildbereiche im Blickfeld und die dadurch hervorgerufene subjektive Einschränkung; die zentralen 20 Grad müssen doppelbildfrei sein.Absolute homonyme Gesichtsfeldausfälle, sowohl als Hemianopsie als auch bei Quadrantenausfällen, die bis an das Zentrum heranreichen, sind nach der Fahrerlaubnisverordnung nicht mit dem Führen eines Kraftfahrzeugs zu vereinen. Hieran ändern auch Trainingsmaßnahmen, die subjektiv zu einer problemlosen Orientierung führen, nichts.Grundsätzlich sollte bei wesentlichen Störungen des Sehvermögens die zusätzliche Expertise eines Augenarztes eingeholt werden, ehe positiv über die Fahrtauglichkeit entschieden wird.

PURPOSE. To assess the occurrence and the disease expression of the common p.Asn1868Ile variant in patients with Stargardt disease (STGD1) harboring known, monoallelic causal ABCA4 variants.METHODS. The coding and noncoding regions of ABCA4 were sequenced in 67 and 63 STGD1 probands respectively, harboring monoallelic ABCA4 variants. In case p.Asn1868Ile was detected, segregation analysis was performed whenever possible. Probands and affected siblings harboring p.Asn1868Ile without additional variants in cis were clinically evaluated retrospectively. Two asymptomatic siblings carrying the same ABCA4 variants as their probands were clinically examined. The penetrance of p.Asn1868Ile was calculated using allele frequency data of ABCA4 variants in non-Finnish European individuals.RESULTS. The p.Asn1868Ile variant was found in cis with known variants in 14/67 probands. In 27/67 probands, we identified p.Asn1868Ile without additional variants in cis, in combination with known, mainly severe ABCA4 variants. In 23/27 probands, the trans configuration was established. Among 27 probands and 6/7 STGD1 siblings carrying p.Asn1868Ile, 42% manifested late-onset disease (> 44 years). We additionally identified four asymptomatic relatives carrying a combination of a severe variant and p.Asn1868Ile; ophthalmologic examination in two persons did not reveal STGD1. Based on ABCA4 allele frequency data, we conservatively estimated the penetrance of p.Asn1868Ile, when present in trans with a severe variant, to be below 5%.CONCLUSIONS. A significant fraction of genetically unexplained STGD1 cases carries p.Asn1868Ile as a second variant. Our findings suggest exceptional differences in disease expression or even nonpenetrance of this ABCA4 variant, pointing toward an important role for genetic or environmental modifiers in STGD1.

Closed-circuit television systems (CCTVs) have become an indispensable tool in rehabilitating low vision patients. Compared to optical visual aids, apart from providing maximum magnification these devices have the additional advantage of improved contrast sensitivity and an enlarged field of view. They are often the only visual aid enabling patients to regain reading ability. Our data reflect a decrease in the number of prescriptions caused by improved counseling of low-vision patients. Any prescription of reading aids must be preceded by comprehensive testing and counseling. More recent developments, such as electronic magnifiers are becoming increasingly more important but they are no substitute for CCTV.

This multicenter, open-label study aimed to determine the safety and functional outcome of a high-addition segmented refractive bifocal intraocular lens (IOL) in late inactive age-related macular degeneration (AMD). Twenty eyes of 20 patients were enrolled and followed until 12 months after the intervention. Patients underwent cataract surgery with implantation of a LS-313 MF80 segmented refractive bifocal intraocular lens with a near addition of +8.0 D (Teleon Surgical Vertriebs GmbH, Berlin, Germany). The main outcome measures were distance corrected near visual acuity (DCNVA) and safety as determined by intra- and post-operative complications. Secondary outcomes included distance corrected visual acuity (CDVA), uncorrected distance visual acuity (UDVA), uncorrected near visual acuity (UNVA), the need for magnification to read newspaper, preferred reading distance, speed and performance (logRAD), as well as patient satisfaction. Mean DCNVA improved from 0.95 (±0.19) to 0.74 (±0.35) logMAR, until 6 months after surgery, P 2 lines of CDVA between 6 and 12 months, in another case, the study IOL was exchanged for a monofocal one due to dysphotopsia and decreased CDVA. Implantation of a segmented refractive bifocal IOL with +8.0 D addition improves near and distance vision in patients with late AMD and has a satisfactory safety profile.

Glaucoma is considered a chronic disease that requires lifelong management. Chronic diseases are known to be highly associated with psychological disturbances such as depression and anxiety. There have also been many studies on association between anxiety or depression and glaucoma. The majority of these studies explained that the glaucoma diagnosis causes anxiety or depression. However, It is also necessary to evaluate whether the psychological disturbance itself affect glaucoma. Therefore, we investigated the association of anxiety and depression with glaucoma progression, and elucidate mechanisms underlying that. We included 251 eyes with open angle glaucoma who were followed up for at least 2 years in this retrospective case-control study. The Beck Anxiety Inventory (BAI) and Beck Depressive Inventory-II (BDI-II) were used to assess anxiety and depression in glaucoma patients. Patients were classified into groups (high-anxiety group; HA-G, low-anxiety group; LA-G, high-depression group; HD-G, low-depression group; LD-G) according to their score on the BAI or BDI-II (separately). In logistic regression analysis, disc hemorrhage, peak intraocular pressure (IOP) and RNFL thickness loss rate were significantly associated with high anxiety (p = 0.017, p = 0.046, p = 0.026). RNFL thinning rate and disc hemorrhage were significant factors associated with anxiety in multivariate models (p = 0.015, p = 0.019). Multivariate linear regression analysis showed a significant positive correlation between the rate of RNFL thickness loss and BAI score (B = 0.058; 95% confidential interval = 0.020–0.097; p = 0.003), and RNFL loss and IOP fluctuation (B = 0.092; 95% confidential interval = 0.030–0.154; p = 0.004). For the depression scale, visual field mean deviation and heart rate variability were significantly associated with high depression in multivariate logistic regression analysis (p = 0.003, p = 0.006). We suggest that anxiety increase the risk of glaucoma progression and they are also associated with IOP profile and disc hemorrhage.

This review focuses on best practices and recommendations for hygiene and disinfection to limit exposure and transmission of infection in outpatient glaucoma clinics during the current CO­VID-19 pandemic.

Background Combined retinal degeneration and sensorineural hearing impairment is mostly due to autosomal recessive Usher syndrome (USH1: congenital deafness, early retinitis pigmentosa (RP); USH2: progressive hearing impairment, RP). Methods Sanger sequencing and NGS of 112 genes (Usher syndrome, nonsyndromic deafness, overlapping conditions), MLPA, and array-CGH were conducted in 138 patients clinically diagnosed with Usher syndrome. Results A molecular diagnosis was achieved in 97% of both USH1 and USH2 patients, with biallelic mutations in 97% (USH1) and 90% (USH2), respectively. Quantitative readout reliably detected CNVs (confirmed by MLPA or array-CGH), qualifying targeted NGS as one tool for detecting point mutations and CNVs. CNVs accounted for 10% of identified USH2A alleles, often in trans to seemingly monoallelic point mutations. We demonstrate PTC124-induced read-through of the common p.Trp3955* nonsense mutation (13% of detected USH2A alleles), a potential therapy target. Usher gene mutations were found in most patients with atypical Usher syndrome, but the diagnosis was adjusted in case of double homozygosity for mutations in OTOA and NR2E3, genes implicated in isolated deafness and RP. Two patients with additional enamel dysplasia had biallelic PEX26 mutations, for the first time linking this gene to Heimler syndrome. Conclusion Targeted NGS not restricted to Usher genes proved beneficial in uncovering conditions mimicking Usher syndrome.

Introduction: The rate of unknown glaucoma is around 50% in industrialized countries. The purpose of our study was to estimate the prevalence of unknown cases of ocular hypertension, glaucoma suspects, and glaucoma in patients consulting for refractive disorders in France. Methods: A retrospective study in the Point Vision ophthalmology center was led in Toulouse, France. All participants consulting for refractive disorders between June 2015 and June 2017 in the ophthalmology center were included. The cases were identified by the assessment of intraocular pressure, optic nerve head structure, and visual field. Ocular hypertension was defined as an intraocular pressure >21 mm Hg. Glaucoma was defined as the association of a glaucomatous papilla and two successive pathological visual fields. Glaucoma suspect was defined as the association of a glaucomatous papilla without visual field defect. The primary endpoint was the prevalence of unknown ocular hypertension, glaucoma suspects, and glaucoma in patients seen in an ophthalmology center. Results: A total of 66,068 patients (mean age = 37 years) consulted for a refraction visual assessment during the study period. Among them, 234 had a visual field and a retinal nerve fiber layer assessment for ocular hypertension and/or suspicious papilla. The prevalence of unknown cases of ocular hypertension, glaucoma suspect, and glaucoma was 2.6, 0.8, and 0.5 per 1,000 consultants, respectively. Median age at diagnosis of ocular hypertension, glaucoma suspect, and glaucoma was 52, 53, and 65 years, respectively. Conclusion: The present study highlights the importance of glaucoma screening in people over 40 years old with the measurement of intraocular pressure and an optic nerve head assessment.

Landolt rings are commonly used for the measurement of visual acuity, especially for legal purposes. For multiple reasons, in clinical practice these optotypes are not in use and not practical. Therefore, the difference between visual acuity tested with Landolt rings as opposed to numbers was evaluated.Visual acuity measurements of 2335 eyes from 1394 patients (aged 5-98 years, median 51 years) were retrospectively analyzed at the Low Vision Department of the University of Heidelberg. The patients had a broad range of ophthalmological disorders. In all patients the measurement of visual acuity was performed with numbers as well as Landolt rings according to DIN 58220. Visual acuity was determined in LogMAR and compared between the two optotypes.Correlation between both optotypes was high with rWhereas in clinical practice visual acuity is typically determined using numbers and early treatment diabetic retinopathy study (ETDRS) charts are the gold standard for a scientific assessment of visual acuity, only the use of Landolt rings enables an examination without the influence of form recognition. The use of Landolt rings is therefore valid for legal reasons in Europe according to EN ISO 8596 and in Germany according to DIN 58220. Comparing Landolt rings with the Snellen E chart or LEA symbols, these results confirm previous reports that visual acuity measured with Landolt rings results in lower visual acuity. On average visual acuity is approximately one line worse than when tested with numbers, a fact that has to be taken into account when comparing different examination results. This may be explained by incorrect correlation of the used numbers exceeding the allowed difference in eligibility of 0.05 LogMAR. Hence, it is important for legal assessment to measure visual acuity correctly with Landolt rings.

Item does not contain fulltext PURPOSE: To elucidate the functional effect of the ABCA4 variant c.5461-10T-->C, one of the most frequent variants associated with Stargardt disease (STGD1). DESIGN: Case series. PARTICIPANTS: Seventeen persons with STGD1 carrying ABCA4 variants and 1 control participant. METHODS: Haplotype analysis of 4 homozygotes and 11 heterozygotes for c.5461-10T-->C and sequence analysis of the ABCA4 gene for a homozygous proband. Fibroblasts were reprogrammed from 3 persons with STGD1 into induced pluripotent stem cells, which were differentiated into photoreceptor progenitor cells (PPCs). The effect of the c.5461-10T-->C variant on RNA splicing by reverse-transcription polymerase chain reaction was analyzed using PPC mRNA. In vitro assays were performed with minigene constructs containing ABCA4 exon 39. We analyzed the natural history and ophthalmologic characteristics of 4 persons homozygous for c.5461-10T-->C. MAIN OUTCOME MEASURES: Haplotype and rare variant data for ABCA4, RNA splice defects, age at diagnosis, visual acuity, fundus appearance, visual field, electroretinography (ERG) results, fluorescein angiography results, and fundus autofluorescence findings. RESULTS: The frequent ABCA4 variant c.5461-10T-->C has a subtle effect on splicing based on prediction programs. A founder haplotype containing c.5461-10T-->C was found to span approximately 96 kb of ABCA4 and did not contain other rare sequence variants. Patient-derived PPCs showed skipping of exon 39 or exons 39 and 40 in the mRNA. HEK293T cell transduction with minigenes carrying exon 39 showed that the splice defects were the result of the c.5461-10T-->C variant. All 4 subjects carrying the c.5461-10T-->C variant in a homozygous state showed a young age of STGD1 onset, with low visual acuity at presentation and abnormal cone ERG results. All 4 demonstrated severe cone-rod dystrophy before 20 years of age and were legally blind by 25 years of age. CONCLUSIONS: The ABCA4 variant c.5461-10T-->C is located on a founder haplotype lacking other disease-causing rare sequence variants. In vitro studies revealed that it leads to mRNA exon skipping and ABCA4 protein truncation. Given the severe phenotype in persons homozygous for this variant, we conclude that this variant results in the absence of ABCA4 activity.

The requirements regarding visual functioning needed for driving ability are stipulated in Annex 6 of the German driving licence regulations: In case of a visual disorder an ophthalmological assessment is essential: It is of crucial importance for the examining ophthalmologist to exhaust all ocular-medical possibilities to enable the applicant to maintain or regain his driving permission. In the overwhelming majority of the cases this is eminently feasible.However, there is no way to attest driving ability in a patient suffering acute one-sided visual loss for a period of 3 months on the basis of legal recommendations. Concerning oculomotor disturbances, the expansion of the diplopic central visual field and the subjective restriction caused thereby are important: the central 20 degree area must be free of diplopia.According to the German driving license regulations, absolute homonymous visual field defects such as hemianopsia or quadrantic defects affecting the visual centre are incompatible with driving an automobile. Even training measures causing the patient to experience a sense of smooth orientation do nothing to mitigate this fact.Dealing with serious disturbances of visual function, as a matter of principle an ophthalmologist should provide an additional expertise before a positive decision on driving ability is made.Die Anforderungen an das Sehvermögen zur Fahreignung sind in Anlage 6 zur Fahrerlaubnisverordnung festgelegt. Bei Störungen ist in der Regel eine augenärztliche Beurteilung erforderlich. Der begutachtende Augenarzt sollte es als seine primäre Aufgabe ansehen, bei der Beurteilung der Fahrerlaubnis alle augenärztlichen Möglichkeiten auszuschöpfen, den Bewerber um eine Fahrerlaubnis tauglich zu machen oder zu halten. In der überwiegenden Mehrzahl der Fälle gelingt dies auch.Allerdings ist es unvermeidlich, bei plötzlichem schwerwiegendem einseitigem Sehverlust für 3 Monate ab dem Auftreten die gesetzlich vorgeschriebene Fahruntauglichkeit zu attestieren. Bei Motilitätsstörungen entscheiden vor allem die Ausdehnung der Doppelbildbereiche im Blickfeld und die dadurch hervorgerufene subjektive Einschränkung; die zentralen 20 Grad müssen doppelbildfrei sein.Absolute homonyme Gesichtsfeldausfälle, sowohl als Hemianopsie als auch bei Quadrantenausfällen, die bis an das Zentrum heranreichen, sind nach der Fahrerlaubnisverordnung nicht mit dem Führen eines Kraftfahrzeugs zu vereinen. Hieran ändern auch Trainingsmaßnahmen, die subjektiv zu einer problemlosen Orientierung führen, nichts.Grundsätzlich sollte bei wesentlichen Störungen des Sehvermögens die zusätzliche Expertise eines Augenarztes eingeholt werden, ehe positiv über die Fahrtauglichkeit entschieden wird.

Hintergrund: Die optische Kohärenztomographie-Angiographie (OCTA) ist eine neue, nichtinvasive Methode, die eine quantitative Beurteilung der retinalen Durchblutung und der Durchblutung am Sehnerv erlaubt. In dieser Arbeit erläutern wir die Grundlagen der Anwendung dieser Methode und geben einen Überblick über die Erkenntnisse, die durch diese Methode bei Glaukom gewonnen wurden. Methoden: Eine selektive Literaturrecherche und Auswertung eigener Daten liegen dieser Arbeit zugrunde. Ergebnisse: Quantitative OCTA-Parameter zeigen eine gute Reproduzierbarkeit bei Glaukompatienten. Glaukompatienten zeigen eine verminderte Flussdichte am Sehnerv sowie im Bereich der Makula im Vergleich zu einer gesunden Kontrollgruppe. Die Flussdichteparameter zeigen insgesamt eine gute diagnostische Diskriminierung. Sie sind aber den strukturellen Parametern, die in der Routinediagnostik angewendet werden, nicht überlegen. Die verminderte Flussdichte korreliert mit dem Ausmaß des strukturellen und funktionellen Glaukomschadens. Schlussfolgerung: Die OCTA ist nichtinvasiv, schnell und reproduzierbar. Erste Ergebnisse von Studien bei Glaukompatienten zeigen das hohe diagnostische Potenzial dieser Methode. In der klinischen Routine könnte die OCTA in Zukunft eine Rolle spielen.

Background: Primary open angle glaucoma and ocular hypertension are habitually treated with eye drops that lower intraocular pressure. Selective laser trabeculoplasty is a safe alternative but is rarely used as first-line treatment. We compared the two.Methods: In this observer-masked, randomised controlled trial treatment-naive patients with open angle glaucoma or ocular hypertension and no ocular comorbidities were recruited between 2012 and 2014 at six UK hospitals. They were randomly allocated (web-based randomisation) to initial selective laser trabeculoplasty or to eye drops. An objective target intraocular pressure was set according to glaucoma severity. The primary outcome was health-related quality of life (HRQoL) at 3 years (assessed by EQ-5D). Secondary outcomes were cost and cost-effectiveness, disease-specific HRQoL, clinical effectiveness, and safety. Analysis was by intention to treat. This study is registered at controlled-trials.com (ISRCTN32038223). Findings: Of 718 patients enrolled, 356 were randomised to the selective laser trabeculoplasty and 362 to the eye drops group. 652 (91%) returned the primary outcome questionnaire at 36 months. Average EQ-5D score was 0·89 (SD 0·18) in the selective laser trabeculoplasty group versus 0·90 (SD 0·16) in the eye drops group, with no significant difference (difference 0·01, 95% CI −0·01 to 0·03; p=0·23). At 36 months, 74·2% (95% CI 69·3-78·6) of patients in the selective laser trabeculoplasty group required no drops to maintain intraocular pressure at target. Eyes of patients in the selective laser trabeculoplasty group were within target intracoluar pressure at more visits (93·0%) than in the eye drops group (91·3%), with glaucoma surgery to lower intraocular pressure required in none versus 11 patients. Over 36 months, from an ophthalmology cost perspective, there was a 97% probability of selective laser trabeculoplasty as first treatment being more cost-effective than eye drops first at a willingness to pay of £20 000 per quality-adjusted life-year gained. Interpretation: Selective laser trabeculoplasty should be offered as a first-line treatment for open angle glaucoma and ocular hypertension, supporting a change in clinical practice. Funding: National Institute for Health Research, Health and Technology Assessment Programme.

Several genes have been implicated in the autosomal recessive form of cone-rod dystrophy (CRD), but the majority of cases remain unsolved. We identified a homozygous interval comprising two known genes associated with the autosomal recessive form of CRD, namely RAB28 and PROM1, in a consanguineous family with clinical evidence of CRD. Both genes proved to be mutation negative upon sequencing of exons and canonical splice sites but whole-genome sequencing revealed a private variant located deep in intron 18 of PROM1. In silico and functional analyses of this variant using minigenes as splicing reporters revealed the integration of a pseudoexon in the mutant transcript, thereby leading to a premature termination codon and presumably resulting in a functional null allele. This is the first report of a deep intronic variant that acts as a splicing mutation in PROM1. The detection of such variants escapes the exon-focused techniques typically used in genetic analyses. Sequencing the entire genomic regions of known disease genes might identify more causal mutations in the autosomal recessive form of CRD.

Purpose: To evaluate papillary, peripapillary, and macular vasculature with optical coherence tomography angiography in preperimetric (PPG), primary open-angle glaucoma (POAG), and normal eyes, and to assess diagnostic ability and associations among the vasculature and structural damage. Methods: This was an observational, cross-sectional study. Retinal nerve fiber layer (RNFL), ganglion cell complex thickness, whole-image (wiVD), inside disc (idVD), peripapillary (ppVD), and macular vessel densities were obtained. Analysis of variance, post hoc test, and Pearson coefficient were used. The areas under the receiver operating characteristic curve (AUC) and cut-offs were calculated. Results: Thirteen healthy, 39 PPG, and 19 POAG eyes were included. Papillary and peripapillary VD were lower in POAG eyes in all parameters analyzed. wiVD in PPG eyes (52.37 ± 5.04%) was significantly decreased compared to healthy eyes (58.02 ± 2.02%, p < 0.05). AUC ranged from 0.62 to 0.90; the established cut-off values were 56% for wiVD, 55% for idVD, and 62% for ppVD. Pearson's correlation coefficient showed a direct correlation between the papillary or peripapillary VD and RNFL thickness. Conclusions: Vessel densities in POAG eyes are significantly lower than in healthy eyes, and they show good discriminatory abilities. A diminished microvascular network is associated with RNFL thinning more strongly in POAG than in PPG eyes.

Background: We assessed bleb morphology and the intraocular pressure(IOP)-lowering effect of trabeculectomy with ologen compared to mitomycin C (MMC) in juvenile open-angle glaucoma (JOAG). Methods: This is a prospective interventional comparative study conducted on 40 eyes (20 patients) with medically uncontrolled JOAG, randomly operating one eye for trabeculectomy with ologen (group A: 20 eyes) and the other with MMC (group B: 20 eyes). IOP measurement, SITA standard perimetry, and spectral domain optical coherence tomography (OCT) for retinal nerve fiber layer (RNFL) thickness were all done pre- and postoperatively. Postoperative blebs were assessed clinically using the Moorfields bleb grading system (MBGS) and anterior segment OCT (AS-OCT). All patients were examined for up to 1 year postoperatively. Results: The mean postoperative IOP was statistically significantly lower than the mean preoperative IOP at each follow-up in each group. At 1 year, the mean postoperative IOP was significantly lower in group A. According to the MBGS, blebs with an ologen implant showed significantly better scoring than those with MMC. AS-OCT showed that ologen-induced blebs had significantly more fluid-filled spaces, cleavage planes, and less fibrosis. Conclusion: Ologen resulted in a lower long-term postoperative IOP, a better bleb morphology, and fewer complications. Our results suggest that ologen may be a useful alternative to MMC in JOAG.

Table of contents O1 The metabolomics approach to autism: identification of biomarkers for early detection of autism spectrum disorder A. K. Srivastava, Y. Wang, R. Huang, C. Skinner, T. Thompson, L. Pollard, T. Wood, F. Luo, R. Stevenson O2 Phenome-wide association study for smoking- and drinking-associated genes in 26,394 American women with African, Asian, European, and Hispanic descents R. Polimanti, J. Gelernter O3 Effects of prenatal environment, genotype and DNA methylation on birth weight and subsequent postnatal outcomes: findings from GUSTO, an Asian birth cohort X. Lin, I. Y. Lim, Y. Wu, A. L. Teh, L. Chen, I. M. Aris, S. E. Soh, M. T. Tint, J. L. MacIsaac, F. Yap, K. Kwek, S. M. Saw, M. S. Kobor, M. J. Meaney, K. M. Godfrey, Y. S. Chong, J. D. Holbrook, Y. S. Lee, P. D. Gluckman, N. Karnani, GUSTO study group O4 High-throughput identification of specific qt interval modulating enhancers at the SCN5A locus A. Kapoor, D. Lee, A. Chakravarti O5 Identification of extracellular matrix components inducing cancer cell migration in the supernatant of cultivated mesenchymal stem cells C. Maercker, F. Graf, M. Boutros O6 Single cell allele specific expression (ASE) IN T21 and common trisomies: a novel approach to understand DOWN syndrome and other aneuploidies G. Stamoulis, F. Santoni, P. Makrythanasis, A. Letourneau, M. Guipponi, N. Panousis, M. Garieri, P. Ribaux, E. Falconnet, C. Borel, S. E. Antonarakis O7 Role of microRNA in LCL to IPSC reprogramming S. Kumar, J. Curran, J. Blangero O8 Multiple enhancer variants disrupt gene regulatory network in Hirschsprung disease S. Chatterjee, A. Kapoor, J. Akiyama, D. Auer, C. Berrios, L. Pennacchio, A. Chakravarti O9 Metabolomic profiling for the diagnosis of neurometabolic disorders T. R. Donti, G. Cappuccio, M. Miller, P. Atwal, A. Kennedy, A. Cardon, C. Bacino, L. Emrick, J. Hertecant, F. Baumer, B. Porter, M. Bainbridge, P. Bonnen, B. Graham, R. Sutton, Q. Sun, S. Elsea O10 A novel causal methylation network approach to Alzheimer’s disease Z. Hu, P. Wang, Y. Zhu, J. Zhao, M. Xiong, David A Bennett O11 A microRNA signature identifies subtypes of triple-negative breast cancer and reveals MIR-342-3P as regulator of a lactate metabolic pathway A. Hidalgo-Miranda, S. Romero-Cordoba, S. Rodriguez-Cuevas, R. Rebollar-Vega, E. Tagliabue, M. Iorio, E. D’Ippolito, S. Baroni O12 Transcriptome analysis identifies genes, enhancer RNAs and repetitive elements that are recurrently deregulated across multiple cancer types B. Kaczkowski, Y. Tanaka, H. Kawaji, A. Sandelin, R. Andersson, M. Itoh, T. Lassmann, the FANTOM5 consortium, Y. Hayashizaki, P. Carninci, A. R. R. Forrest O13 Elevated mutation and widespread loss of constraint at regulatory and architectural binding sites across 11 tumour types C. A. Semple O14 Exome sequencing provides evidence of pathogenicity for genes implicated in colorectal cancer E. A. Rosenthal, B. Shirts, L. Amendola, C. Gallego, M. Horike-Pyne, A. Burt, P. Robertson, P. Beyers, C. Nefcy, D. Veenstra, F. Hisama, R. Bennett, M. Dorschner, D. Nickerson, J. Smith, K. Patterson, D. Crosslin, R. Nassir, N. Zubair, T. Harrison, U. Peters, G. Jarvik, NHLBI GO Exome Sequencing Project O15 The tandem duplicator phenotype as a distinct genomic configuration in cancer F. Menghi, K. Inaki, X. Woo, P. Kumar, K. Grzeda, A. Malhotra, H. Kim, D. Ucar, P. Shreckengast, K. Karuturi, J. Keck, J. Chuang, E. T. Liu O16 Modeling genetic interactions associated with molecular subtypes of breast cancer B. Ji, A. Tyler, G. Ananda, G. Carter O17 Recurrent somatic mutation in the MYC associated factor X in brain tumors H. Nikbakht, M. Montagne, M. Zeinieh, A. Harutyunyan, M. Mcconechy, N. Jabado, P. Lavigne, J. Majewski O18 Predictive biomarkers to metastatic pancreatic cancer treatment J. B. Goldstein, M. Overman, G. Varadhachary, R. Shroff, R. Wolff, M. Javle, A. Futreal, D. Fogelman O19 DDIT4 gene expression as a prognostic marker in several malignant tumors L. Bravo, W. Fajardo, H. Gomez, C. Castaneda, C. Rolfo, J. A. Pinto O20 Spatial organization of the genome and genomic alterations in human cancers K. C. Akdemir, L. Chin, A. Futreal, ICGC PCAWG Structural Alterations Group O21 Landscape of targeted therapies in solid tumors S. Patterson, C. Statz, S. Mockus O22 Genomic analysis reveals novel drivers and progression pathways in skin basal cell carcinoma S. N. Nikolaev, X. I. Bonilla, L. Parmentier, B. King, F. Bezrukov, G. Kaya, V. Zoete, V. Seplyarskiy, H. Sharpe, T. McKee, A. Letourneau, P. Ribaux, K. Popadin, N. Basset-Seguin, R. Ben Chaabene, F. Santoni, M. Andrianova, M. Guipponi, M. Garieri, C. Verdan, K. Grosdemange, O. Sumara, M. Eilers, I. Aifantis, O. Michielin, F. de Sauvage, S. Antonarakis O23 Identification of differential biomarkers of hepatocellular carcinoma and cholangiocarcinoma via transcriptome microarray meta-analysis S. Likhitrattanapisal O24 Clinical validity and actionability of multigene tests for hereditary cancers in a large multi-center study S. Lincoln, A. Kurian, A. Desmond, S. Yang, Y. Kobayashi, J. Ford, L. Ellisen O25 Correlation with tumor ploidy status is essential for correct determination of genome-wide copy number changes by SNP array T. L. Peters, K. R. Alvarez, E. F. Hollingsworth, D. H. Lopez-Terrada O26 Nanochannel based next-generation mapping for interrogation of clinically relevant structural variation A. Hastie, Z. Dzakula, A. W. Pang, E. T. Lam, T. Anantharaman, M. Saghbini, H. Cao, BioNano Genomics O27 Mutation spectrum in a pulmonary arterial hypertension (PAH) cohort and identification of associated truncating mutations in TBX4 C. Gonzaga-Jauregui, L. Ma, A. King, E. Berman Rosenzweig, U. Krishnan, J. G. Reid, J. D. Overton, F. Dewey, W. K. Chung O28 NORTH CAROLINA macular dystrophy (MCDR1): mutations found affecting PRDM13 K. Small, A. DeLuca, F. Cremers, R. A. Lewis, V. Puech, B. Bakall, R. Silva-Garcia, K. Rohrschneider, M. Leys, F. S. Shaya, E. Stone O29 PhenoDB and genematcher, solving unsolved whole exome sequencing data N. L. Sobreira, F. Schiettecatte, H. Ling, E. Pugh, D. Witmer, K. Hetrick, P. Zhang, K. Doheny, D. Valle, A. Hamosh O30 Baylor-Johns Hopkins Center for Mendelian genomics: a four year review S. N. Jhangiani, Z. Coban Akdemir, M. N. Bainbridge, W. Charng, W. Wiszniewski, T. Gambin, E. Karaca, Y. Bayram, M. K. Eldomery, J. Posey, H. Doddapaneni, J. Hu, V. R. Sutton, D. M. Muzny, E. A. Boerwinkle, D. Valle, J. R. Lupski, R. A. Gibbs O31 Using read overlap assembly to accurately identify structural genetic differences in an ashkenazi jewish trio S. Shekar, W. Salerno, A. English, A. Mangubat, J. Bruestle O32 Legal interoperability: a sine qua non for international data sharing A. Thorogood, B. M. Knoppers, Global Alliance for Genomics and Health - Regulatory and Ethics Working Group O33 High throughput screening platform of competent sineups: that can enhance translation activities of therapeutic target H. Takahashi, K. R. Nitta, A. Kozhuharova, A. M. Suzuki, H. Sharma, D. Cotella, C. Santoro, S. Zucchelli, S. Gustincich, P. Carninci O34 The undiagnosed diseases network international (UDNI): clinical and laboratory research to meet patient needs J. J. Mulvihill, G. Baynam, W. Gahl, S. C. Groft, K. Kosaki, P. Lasko, B. Melegh, D. Taruscio O36 Performance of computational algorithms in pathogenicity predictions for activating variants in oncogenes versus loss of function mutations in tumor suppressor genes R. Ghosh, S. Plon O37 Identification and electronic health record incorporation of clinically actionable pharmacogenomic variants using prospective targeted sequencing S. Scherer, X. Qin, R. Sanghvi, K. Walker, T. Chiang, D. Muzny, L. Wang, J. Black, E. Boerwinkle, R. Weinshilboum, R. Gibbs O38 Melanoma reprogramming state correlates with response to CTLA-4 blockade in metastatic melanoma T. Karpinets, T. Calderone, K. Wani, X. Yu, C. Creasy, C. Haymaker, M. Forget, V. Nanda, J. Roszik, J. Wargo, L. Haydu, X. Song, A. Lazar, J. Gershenwald, M. Davies, C. Bernatchez, J. Zhang, A. Futreal, S. Woodman O39 Data-driven refinement of complex disease classification from integration of heterogeneous functional genomics data in GeneWeaver E. J. Chesler, T. Reynolds, J. A. Bubier, C. Phillips, M. A. Langston, E. J. Baker O40 A general statistic framework for genome-based disease risk prediction M. Xiong, L. Ma, N. Lin, C. Amos O41 Integrative large-scale causal network analysis of imaging and genomic data and its application in schizophrenia studies N. Lin, P. Wang, Y. Zhu, J. Zhao, V. Calhoun, M. Xiong O42 Big data and NGS data analysis: the cloud to the rescue O. Dobretsberger, M. Egger, F. Leimgruber O43 Cpipe: a convergent clinical exome pipeline specialised for targeted sequencing S. Sadedin, A. Oshlack, Melbourne Genomics Health Alliance O44 A Bayesian classification of biomedical images using feature extraction from deep neural networks implemented on lung cancer data V. A. A. Antonio, N. Ono, Clark Kendrick C. Go O45 MAV-SEQ: an interactive platform for the Management, Analysis, and Visualization of sequence data Z. Ahmed, M. Bolisetty, S. Zeeshan, E. Anguiano, D. Ucar O47 Allele specific enhancer in EPAS1 intronic regions may contribute to high altitude adaptation of Tibetans C. Zeng, J. Shao O48 Nanochannel based next-generation mapping for structural variation detection and comparison in trios and populations H. Cao, A. Hastie, A. W. Pang, E. T. Lam, T. Liang, K. Pham, M. Saghbini, Z. Dzakula O49 Archaic introgression in indigenous populations of Malaysia revealed by whole genome sequencing Y. Chee-Wei, L. Dongsheng, W. Lai-Ping, D. Lian, R. O. Twee Hee, Y. Yunus, F. Aghakhanian, S. S. Mokhtar, C. V. Lok-Yung, J. Bhak, M. Phipps, X. Shuhua, T. Yik-Ying, V. Kumar, H. Boon-Peng O50 Breast and ovarian cancer prevention: is it time for population-based mutation screening of high risk genes? I. Campbell, M.-A. Young, P. James, Lifepool O53 Comprehensive coverage from low DNA input using novel NGS library preparation methods for WGS and WGBS C. Schumacher, S. Sandhu, T. Harkins, V. Makarov O54 Methods for large scale construction of robust PCR-free libraries for sequencing on Illumina HiSeqX platform H. DoddapaneniR. Glenn, Z. Momin, B. Dilrukshi, H. Chao, Q. Meng, B. Gudenkauf, R. Kshitij, J. Jayaseelan, C. Nessner, S. Lee, K. Blankenberg, L. Lewis, J. Hu, Y. Han, H. Dinh, S. Jireh, K. Walker, E. Boerwinkle, D. Muzny, R. Gibbs O55 Rapid capture methods for clinical sequencing J. Hu, K. Walker, C. Buhay, X. Liu, Q. Wang, R. Sanghvi, H. Doddapaneni, Y. Ding, N. Veeraraghavan, Y. Yang, E. Boerwinkle, A. L. Beaudet, C. M. Eng, D. M. Muzny, R. A. Gibbs O56 A diploid personal human genome model for better genomes from diverse sequence data K. C. C. Worley, Y. Liu, D. S. T. Hughes, S. C. Murali, R. A. Harris, A. C. English, X. Qin, O. A. Hampton, P. Larsen, C. Beck, Y. Han, M. Wang, H. Doddapaneni, C. L. Kovar, W. J. Salerno, A. Yoder, S. Richards, J. Rogers, J. R. Lupski, D. M. Muzny, R. A. Gibbs O57 Development of PacBio long range capture for detection of pathogenic structural variants Q. Meng, M. Bainbridge, M. Wang, H. Doddapaneni, Y. Han, D. Muzny, R. Gibbs O58 Rhesus macaques exhibit more non-synonymous variation but greater impact of purifying selection than humans R. A. Harris, M. Raveenedran, C. Xue, M. Dahdouli, L. Cox, G. Fan, B. Ferguson, J. Hovarth, Z. Johnson, S. Kanthaswamy, M. Kubisch, M. Platt, D. Smith, E. Vallender, R. Wiseman, X. Liu, J. Below, D. Muzny, R. Gibbs, F. Yu, J. Rogers O59 Assessing RNA structure disruption induced by single-nucleotide variation J. Lin, Y. Zhang, Z. Ouyang P1 A meta-analysis of genome-wide association studies of mitochondrial dna copy number A. Moore, Z. Wang, J. Hofmann, M. Purdue, R. Stolzenberg-Solomon, S. Weinstein, D. Albanes, C.-S. Liu, W.-L. Cheng, T.-T. Lin, Q. Lan, N. Rothman, S. Berndt P2 Missense polymorphic genetic combinations underlying down syndrome susceptibility E. S. Chen P4 The evaluation of alteration of ELAM-1 expression in the endometriosis patients H. Bahrami, A. Khoshzaban, S. Heidari Keshal P5 Obesity and the incidence of apolipoprotein E polymorphisms in an assorted population from Saudi Arabia population K. K. R. Alharbi P6 Genome-associated personalized antithrombotical therapy for patients with high risk of thrombosis and bleeding M. Zhalbinova, A. Akilzhanova, S. Rakhimova, M. Bekbosynova, S. Myrzakhmetova P7 Frequency of Xmn1 polymorphism among sickle cell carrier cases in UAE population M. Matar P8 Differentiating inflammatory bowel diseases by using genomic data: dimension of the problem and network organization N. Mili, R. Molinari, Y. Ma, S. Guerrier P9 Vulnerability of genetic variants to the risk of autism among Saudi children N. Elhawary, M. Tayeb, N. Bogari, N. Qotb P10 Chromatin profiles from ex vivo purified dopaminergic neurons establish a promising model to support studies of neurological function and dysfunction S. A. McClymont, P. W. Hook, L. A. Goff, A. McCallion P11 Utilization of a sensitized chemical mutagenesis screen to identify genetic modifiers of retinal dysplasia in homozygous Nr2e3rd7 mice Y. Kong, J. R. Charette, W. L. Hicks, J. K. Naggert, L. Zhao, P. M. Nishina P12 Ion torrent next generation sequencing of recessive polycystic kidney disease in Saudi patients B. M. Edrees, M. Athar, F. A. Al-Allaf, M. M. Taher, W. Khan, A. Bouazzaoui, N. A. Harbi, R. Safar, H. Al-Edressi, A. Anazi, N. Altayeb, M. A. Ahmed, K. Alansary, Z. Abduljaleel P13 Digital expression profiling of Purkinje neurons and dendrites in different subcellular compartments A. Kratz, P. Beguin, S. Poulain, M. Kaneko, C. Takahiko, A. Matsunaga, S. Kato, A. M. Suzuki, N. Bertin, T. Lassmann, R. Vigot, P. Carninci, C. Plessy, T. Launey P14 The evolution of imperfection and imperfection of evolution: the functional and functionless fractions of the human genome D. Graur P16 Species-independent identification of known and novel recurrent genomic entities in multiple cancer patients J. Friis-Nielsen, J. M. Izarzugaza, S. Brunak P18 Discovery of active gene modules which are densely conserved across multiple cancer types reveal their prognostic power and mutually exclusive mutation patterns B. S. Soibam P19 Whole exome sequencing of dysplastic leukoplakia tissue indicates sequential accumulation of somatic mutations from oral precancer to cancer D. Das, N. Biswas, S. Das, S. Sarkar, A. Maitra, C. Panda, P. Majumder P21 Epigenetic mechanisms of carcinogensis by hereditary breast cancer genes J. J. Gruber, N. Jaeger, M. Snyder P22 RNA direct: a novel RNA enrichment strategy applied to transcripts associated with solid tumors K. Patel, S. Bowman, T. Davis, D. Kraushaar, A. Emerman, S. Russello, N. Henig, C. Hendrickson P23 RNA sequencing identifies gene mutations for neuroblastoma K. Zhang P24 Participation of SFRP1 in the modulation of TMPRSS2-ERG fusion gene in prostate cancer cell lines M. Rodriguez-Dorantes, C. D. Cruz-Hernandez, C. D. P. Garcia-Tobilla, S. Solorzano-Rosales P25 Targeted Methylation Sequencing of Prostate Cancer N. Jäger, J. Chen, R. Haile, M. Hitchins, J. D. Brooks, M. Snyder P26 Mutant TPMT alleles in children with acute lymphoblastic leukemia from México City and Yucatán, Mexico S. Jiménez-Morales, M. Ramírez, J. Nuñez, V. Bekker, Y. Leal, E. Jiménez, A. Medina, A. Hidalgo, J. Mejía P28 Genetic modifiers of Alström syndrome J. Naggert, G. B. Collin, K. DeMauro, R. Hanusek, P. M. Nishina P31 Association of genomic variants with the occurrence of angiotensin-converting-enzyme inhibitor (ACEI)-induced coughing among Filipinos E. M. Cutiongco De La Paz, R. Sy, J. Nevado, P. Reganit, L. Santos, J. D. Magno, F. E. Punzalan , D. Ona , E. Llanes, R. L. Santos-Cortes , R. Tiongco, J. Aherrera, L. Abrahan, P. Pagauitan-Alan; Philippine Cardiogenomics Study Group P32 The use of “humanized” mouse models to validate disease association of a de novo GARS variant and to test a novel gene therapy strategy for Charcot-Marie-Tooth disease type 2D K. H. Morelli, J. S. Domire, N. Pyne, S. Harper, R. Burgess P34 Molecular regulation of chondrogenic human induced pluripotent stem cells M. A. Gari, A. Dallol, H. Alsehli, A. Gari, M. Gari, A. Abuzenadah P35 Molecular profiling of hematologic malignancies: implementation of a variant assessment algorithm for next generation sequencing data analysis and clinical reporting M. Thomas, M. Sukhai, S. Garg, M. Misyura, T. Zhang, A. Schuh, T. Stockley, S. Kamel-Reid P36 Accessing genomic evidence for clinical variants at NCBI S. Sherry, C. Xiao, D. Slotta, K. Rodarmer, M. Feolo, M. Kimelman, G. Godynskiy, C. O’Sullivan, E. Yaschenko P37 NGS-SWIFT: a cloud-based variant analysis framework using control-accessed sequencing data from DBGAP/SRA C. Xiao, E. Yaschenko, S. Sherry P38 Computational assessment of drug induced hepatotoxicity through gene expression profiling C. Rangel-Escareño, H. Rueda-Zarate P40 Flowr: robust and efficient pipelines using a simple language-agnostic approach;ultraseq; fast modular pipeline for somatic variation calling using flowr S. Seth, S. Amin, X. Song, X. Mao, H. Sun, R. G. Verhaak, A. Futreal, J. Zhang P41 Applying “Big data” technologies to the rapid analysis of heterogenous large cohort data S. J. Whiite, T. Chiang, A. English, J. Farek, Z. Kahn, W. Salerno, N. Veeraraghavan, E. Boerwinkle, R. Gibbs P42 FANTOM5 web resource for the large-scale genome-wide transcription start site activity profiles of wide-range of mammalian cells T. Kasukawa, M. Lizio, J. Harshbarger, S. Hisashi, J. Severin, A. Imad, S. Sahin, T. C. Freeman, K. Baillie, A. Sandelin, P. Carninci, A. R. R. Forrest, H. Kawaji, The FANTOM Consortium P43 Rapid and scalable typing of structural variants for disease cohorts W. Salerno, A. English, S. N. Shekar, A. Mangubat, J. Bruestle, E. Boerwinkle, R. A. Gibbs P44 Polymorphism of glutathione S-transferases and sulphotransferases genes in an Arab population A. H. Salem, M. Ali, A. Ibrahim, M. Ibrahim P46 Genetic divergence of CYP3A5*3 pharmacogenomic marker for native and admixed Mexican populations J. C. Fernandez-Lopez, V. Bonifaz-Peña, C. Rangel-Escareño, A. Hidalgo-Miranda, A. V. Contreras P47 Whole exome sequence meta-analysis of 13 white blood cell, red blood cell, and platelet traits L. Polfus, CHARGE and NHLBI Exome Sequence Project Working Groups P48 Association of adipoq gene with type 2 diabetes and related phenotypes in african american men and women: The jackson heart study S. Davis, R. Xu, S. Gebeab, P Riestra, A Gaye, R. Khan, J. Wilson, A. Bidulescu P49 Common variants in casr gene are associated with serum calcium levels in koreans S. H. Jung, N. Vinayagamoorthy, S. H. Yim, Y. J. Chung P50 Inference of multiple-wave population admixture by modeling decay of linkage disequilibrium with multiple exponential functions Y. Zhou, S. Xu P51 A Bayesian framework for generalized linear mixed models in genome-wide association studies X. Wang, V. Philip, G. Carter P52 Targeted sequencing approach for the identification of the genetic causes of hereditary hearing impairment A. A. Abuzenadah, M. Gari, R. Turki, A. Dallol P53 Identification of enhancer sequences by ATAC-seq open chromatin profiling A. Uyar, A. Kaygun, S. Zaman, E. Marquez, J. George, D. Ucar P54 Direct enrichment for the rapid preparation of targeted NGS libraries C. L. Hendrickson, A. Emerman, D. Kraushaar, S. Bowman, N. Henig, T. Davis, S. Russello, K. Patel P56 Performance of the Agilent D5000 and High Sensitivity D5000 ScreenTape assays for the Agilent 4200 Tapestation System R. Nitsche, L. Prieto-Lafuente P57 ClinVar: a multi-source archive for variant interpretation M. Landrum, J. Lee, W. Rubinstein, D. Maglott P59 Association of functional variants and protein physical interactions of human MUTY homolog linked with familial adenomatous polyposis and colorectal cancer syndrome Z. Abduljaleel, W. Khan, F. A. Al-Allaf, M. Athar , M. M. Taher, N. Shahzad P60 Modification of the microbiom constitution in the gut using chicken IgY antibodies resulted in a reduction of acute graft-versus-host disease after experimental bone marrow transplantation A. Bouazzaoui, E. Huber, A. Dan, F. A. Al-Allaf, W. Herr, G. Sprotte, J. Köstler, A. Hiergeist, A. Gessner, R. Andreesen, E. Holler P61 Compound heterozygous mutation in the LDLR gene in Saudi patients suffering severe hypercholesterolemia F. Al-Allaf, A. Alashwal, Z. Abduljaleel, M. Taher, A. Bouazzaoui, H. Abalkhail, A. Al-Allaf, R. Bamardadh, M. Athar

International audience; Retinal dystrophies (RD) constitute a group of blinding diseases that are characterized by clinical variability and pronounced genetic heterogeneity. The different nonsyndromic and syndromic forms of RD can be attributed to mutations in more than 200 genes. Consequently, next generation sequencing (NGS) technologies are among the most promising approaches to identify mutations in RD. We screened a large cohort of patients comprising 89 independent cases and families with various subforms of RD applying different NGS platforms. While mutation screening in 50 cases was performed using a RD gene capture panel, 47 cases were analyzed using whole exome sequencing. One family was analyzed using whole genome sequencing. A detection rate of 61% was achieved including mutations in 34 known and two novel RD genes. A total of 69 distinct mutations were identified, including 39 novel mutations. Notably, genetic findings in several families were not consistent with the initial clinical diagnosis. Clinical reassessment resulted in refinement of the clinical diagnosis in some of these families and confirmed the broad clinical spectrum associated with mutations in RD genes.

The visual functional diagnostics for patients with advanced glaucomatous optic neuropathy are subject to challenge. Reduced visual acuity, instable fixation and extensive scotomata frequently lead to incorrect results within the central 30° or 24° field. Static automatic perimetry (SAP) in particular is often hampered by extended examination time and fatigue especially in older patients. Focusing of the examination towards the central 10° field using a dense test grid (2° distance between stimulus locations) allows a more exact assessment of the small remaining central island. Tailoring the examination area towards the central 10° field may be useful even in cases with a mean deviation (MD) of 15 dB. In cases of advanced visual field loss kinetic perimetry is superior to static perimetry for various reasons: sharply demarcated visual field defects can be comparatively easily delineated (edge detection); the results are more reliable because fixation can be easily controlled and fatigue is much less pronounced in this interactive examination procedure. However, manual kinetic visual field testing within the central 5° using the conventional Goldmann perimeter is almost impossible due to technical reasons. Semi-automated kinetic perimetry, presenting moving stimuli along interactively defined vectors is a useful tool under these circumstances. The standardized presentation of kinetic stimuli is also feasible within the pericentral region and has particular advantages also with regard to follow-up examinations. On the other hand, detection and delineation of small visual field remnants are comparatively difficult to handle with this kind of vector-based kinetic perimetry.

Die Gesichtsfelduntersuchung mittels statischer automatischer Perimetrie (SAP) ist die Methode der Wahl zur Funktionsbestimmung beim Glaukom. Dennoch lassen sich damit beginnende Skotome oft nicht darstellen, selbst wenn es bereits zu morphologisch erkennbaren Schaden der Nervenfaserschicht gekommen ist. Dies gilt insbesondere fur Nervenfaserbundeldefekte. Die Mikroperimetrie oder Fundusperimetrie erlaubt eine gezielte Untersuchung der Lichtunterschiedsempfindlichkeit uber spezifischen, zugehorigen Netzhautarealen. Beim Glaukomschaden muss im Gegensatz zur primaren Schadigung der Rezeptoren der Verlauf der Nervenfasern und die dadurch hervorgerufene Lokalisation des hervorgerufenen Funktionsausfalls berucksichtigt werden. Dabei ist der Nachweis einer Funktionsschadigung moglicherweise fruhzeitiger als mit der konventionellen statischen Schwellenperimetrie moglich. Der zusatzliche Aufwand an Kosten und Zeit hat die Verbreitung der Fundusperimetrie bisher eingeschrankt. Aktuelle Entwicklungen konnten neue Perspektiven bieten.

Ziel: Untersuchung der Frage, ob sich postoperativ die Lichtempfindlichkeit vollständig regeneriert und nach erfolgreicher chirurgischer Behandlung einer rhegmatogenen Netzhautablösung (RNA) auf das Niveau vor deren Entwicklung zurückkehrt. Methoden: Wir untersuchten retrospektiv 44 Augen von 44 Patienten, bei denen eine RNA erfolgreich operiert und nachfolgend eine zentrale 30-2-Humphrey-Perimetrie durchgeführt worden war. Die Durchschnittsabweichung in der Humphrey-Perimetrie in der wiederangelegten Netzhaut wurde mit der horizontalen oder vertikalen Entsprechung in der präoperativ nicht-abgelösten Netzhaut verglichen. Ergebnisse: Die Durchschnittsabweichung in der wiederangelegten Netzhaut war signifikant niedriger als im Vergleichsareal (p < 0,0001). Der gemittelte verbleibende Lichtempfindlichkeitsverlust korrelierte nicht mit der postoperativen Sehschärfe (p = 0,8047) oder deren Veränderung (p = 0,8047). Schlussfolgerungen: Die Lichtempfindlichkeit in der abgelösten Netzhaut in Augen mit RNA regeneriert sich nach erfolgreicher operativer Behandlung nicht vollständig.

Die Bestimmung der Sehscharfe bei sehbehinderten Kindern oder bei Mehrfachbehinderten ist schwierig. In unserer Sehbehindertensprechstunde haben wir ein Testverfahren eingesetzt, bei dem Wurfel unterschiedlicher Grose und Farbe als Objekte prasentiert werden, um daraus die Sehscharfe zu schatzen. Ziel dieser Arbeit war der Vergleich der anhand dieses Wurfel-Tests bestimmten Sehscharfe mit derjenigen, die spater bei entsprechender Mitarbeit mit konventioneller Sehscharfeprufung erhoben wurde. 88 Kinder mit unterschiedlichen nicht fortschreitenden Augenerkrankungen (Albinismus, Netzhautnarben, Fruhgeborenenretinopathie, Achromatopsie, Optikusatrophie u. a.) wurden in diese Longitudinalstudie aufgenommen. Der Median der Verlaufsdauer betrug 8,7 Jahre (2,9 bis 18,9 Jahre). Die erste Untersuchung wurde im Alter von 4 bis 24 Monaten durchgefuhrt (Median 11 Monate). Die Sehscharfe, gemessen in einem Abstand von 30 cm, wurde fur Wurfel mit einer Kantenlange von 4 mm auf 0,1 geschatzt. Die tatsachliche Sehscharfe wurde spater mit bester Korrektur mittels LH-Test, Zahlen- oder Landolt-Visus gemessen und mit obigem Ergebnis verglichen. Zum Ende des 1. Lebensjahrs konnte bei fast allen Kindern eine verwertbare Visusbestimmung mit dem Wurfel-Test durchgefuhrt werden (Median 11 Monate, 4 bis 27 Monate), bei 12 Kindern bereits zwischen dem 4. und 10. Monat. Die Sehscharfe lag zwischen Lichtscheinwahrnehmung und 1,0, mit einem Median von 0,2. Bei 39 Patienten betrug der Visus bei der letzten Kontrolluntersuchung 0,1 oder weniger. Die Sehscharfe, die mit dem Wurfel-Test bis maximal 0,125 gemessen werden kann, wurde lediglich bei 5 Kindern im Vergleich zum spater bestimmten Visus um maximal 3 Visusstufen uberschatzt. Im Visusbereich bis 0,1 war eine sehr hohe Ubereinstimmung feststellbar. Bei keinem Kind wurde ein bestehender Anspruch auf Blindenhilfe falschlich verneint. Selbst ein so einfacher Test wie der hier beschriebene Wurfel-Test erlaubt eine verwertbare Visusbestimmung bei sehbehinderten Kindern und bei Personen mit Einschrankungen, welche die Durchfuhrung einer normalen Sehscharfebestimmung erschweren. Dieser Test berucksichtigt im Vergleich zu Preferential-looking-Verfahren nicht nur die vom Untersucher beobachtete Reaktion, sondern er setzt ein aktives Handeln des Patienten voraus. Bereits zum Ende des 1. Lebensjahrs ist so eine verlassliche Angabe zum Vorliegen einer Sehbehinderung moglich. Damit ist eine gezieltere Beratung der betroffenen Familien und eine schnellere Einleitung einer Fruhfordermasnahme moglich.

Contains fulltext : 81053.pdf (Publisher’s version ) (Closed access) PURPOSE: The purpose of this study was to identify the causative gene defect in two siblings with an uncharacterized cone-rod dysfunction and to describe the clinical characteristics. METHODS: Genome-wide homozygosity mapping, with a 250K SNP-array followed by a search for candidate genes, was performed. The patients underwent ophthalmic examination, including elaborate electroretinography. RESULTS: In a Dutch sib pair, a shared 9-Mb homozygous region was found on 11q13.1-q13.5 that encompasses the CABP4 gene, previously implicated in autosomal recessive incomplete congenital stationary night blindness (CSNB2) in two small families. A novel homozygous p.Arg216X mutation in CABP4 was detected in the sib pair. Quantitative RT-PCR on RNA isolated from patient lymphoblast cells showed no nonsense-mediated degradation of mutant CABP4 mRNA. Clinically, patients presented with reduced visual acuity, photophobia, and abnormal color vision, but they did not experience night blindness. Electroretinograms showed electronegative mixed rod-cone responses and severely reduced cone responses, as in CSNB2. Isolated rod responses, however, were (sub)normal. CONCLUSIONS: A novel homozygous nonsense mutation in CABP4 in two siblings resulted in a phenotype with severely reduced cone function and only negligibly reduced rod function on electroretinography and psychophysical testing. Since these patients and two of three previously described patients do not experience night blindness, the name CSNB2 is confusing for patients as well as clinicians. Therefore, the authors propose to name the phenotype congenital cone-rod synaptic disorder.

The advances in retinal imaging technologies have led to enormous innovation towards diagnostic in current ophthalmology, enabling the practitioner to detect early retinal changes and to document treatment effects. While, in the past, retinoscopy, visual acuity testing and perimetry played the major role in functional diagnostics, today, laser-based systems like laser scanning imaging systems especially for fluorescein-angiography, optical coherence tomography, electrodiagnostic systems and the analysis of retinal vessels may be used as well. However, the challenge to correlate subjective alterations or clinical changes with visual function, still remains. Micro- or fundus perimetry offers the option to test retinal sensitivity while directly observing the fundus. In this paper, we review the literature encompassing the results of more than 25 years of fundus perimetry, i.e. perimetry under simultaneous visualization of the fundus. During this time, results on known diseases and reproducibility of the technique were published, but a lot of work was also performed on the combination of different examination methods, allowing a synopsis of long-term results and new approaches by combining different methods and improving each of them. The first part of this review attends to improvements of the method. The second part addresses the clinical and diagnostic values. The final part is dedicated to diagnostic and long-term observation of fundus perimetric results beginning with common and rare diseases like age-related macular degeneration, macular holes and diabetic retinopathy, various types of macular dystrophies ending with challenges in conventional perimetry like glaucoma and malingering. Due to the experience and progress in the field of fundus perimetry and retinal imaging, the method has long passed its role of observing and has all the potential for prediction, early detection and treatment-monitoring of macular diseases.

For the determination of visual function an objective assessment is essential. Basic ophthalmologic examinations such as measurement of visual acuity and perimetry are dependent on patient statements. If the patient is not being able to provide adequate answers, as is the case for small children or mentally retarded patients, or also if the accuracy of the patient's statements is doubtful or simulation or aggravation is suspected, the denoted function in the evaluation of visual acuity has to be checked on consistency using different examination methods, and the results of objective functional tests, such as electrophysiology and morphological features, have to be taken into account.

Das Microperimeter 1 (MP-1) ermoglicht eine funduskontrollierte statische Schwellenperimetrie des zentralen Gesichtsfelds. Ziel dieser Studie war es, die MP-1-Fundusperimetrie mit der bereits etablierten Scanning-Laser-Ophthalmoskop- (SLO-)Fundusperimetrie hinsichtlich der detektierten Schwellenwerte der Lichtunterschiedsempfindlichkeit (LUE) bei Probanden zu vergleichen. Bei 31 Augen von 31 gesunden Probanden wurde jeweils mit dem MP-1 (Fa. Nidek Technologies, Erlangen) sowie mit dem SLO (Fa. Rodenstock) eine funduskontrollierte statische Perimetrie durchgefuhrt. Im zentralen 21°×12°-Gesichtsfeld wurden in einem rechteckigen 3°-Raster fur 40 korrespondierende Testpunkte die Schwellenwerte der LUE verglichen. Die mittlere LUE betrug am MP-1 19,1±0,5 dB und am SLO 17,2±0,9 dB. Im Durchschnitt lagen die LUE-Schwellenwerte der 40 korrespondierenden Prufpunkte bei der Untersuchung am MP-1 um 1,9±1,3 dB uber denen am SLO. Sowohl das MP-1 als auch das SLO bieten eine reproduzierbare Funktionsanalyse der zentralen Netzhaut bei gleichzeitiger Funduskontrolle. Zum Vergleich von Ergebnissen der MP-1- und SLO-Fundusperimetrie ist ein Korrektionsfaktor von etwa 2 dB anzuwenden.

Hintergrund Kantenfilter konnen bei verschiedenen dystrophischen Netzhautdegenerationen eine Steigerung der Kontrastwahrnehmung bewirken und damit das Sehvermogen verbessern. Wir untersuchten, ob durch Verwendung von speziellen Kantenfiltern eine messbare Verbesserung der Lesefahigkeit bei altersabhangiger Makuladegeneration (AMD) zu erreichen ist.