Inherited retinal diseases (IRDs) are rare disorders, typically presenting as Mendelian traits, that result in stationary or progressive visual impairment. They are characterized by extensive genetic ...

We discovered genetic changes in three genes (AP5Z1, AP5M1, and AP5B1) that cause macular degeneration, affecting sharp central vision. The proteins encoded by these genes form a complex that helps th...

17 January 2025

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Detecting pathogenic germline variants in the clinic remains technically challenging. We analyzed 145 previously identified, hard-to-detect variants in 100 samples using HiFi long-read sequencing (LRS...

The U4 small nuclear RNA (snRNA) forms a duplex with the U6 snRNA and, together with U5 and ∼30 proteins, is part of the U4/U6.U5 tri-snRNP complex, located at the core of the major spliceosome. Recently, recurrent de novo variants in the U4 RNA, transcribed from the RNU4-2 gene, and in at least two other RNU genes were discovered to cause neurodevelopmental disorder. We detected inherited and de novo heterozygous variants in RNU4-2 (n.18\_19insA and n.56T>C) and in four out of the five RNU6 paralogues (n.55\_56insG and n.56_57insG) in 135 individuals from 62 families with non-syndromic retinitis pigmentosa (RP), a rare form of hereditary blindness. We show that these variants are recurrent among RP families and invariably cluster in close proximity within the three-way junction (between stem-I, the 5’ stem-loop and stem-II) of the U4/U6 duplex, affecting its natural conformation. Interestingly, this region binds to numerous splicing factors of the tri-snRNP complex including PRPF3, PRPF8 and PRPF31, previously associated with RP as well. The U4 and U6 variants identified seem to affect snRNP biogenesis, namely the U4/U6 di-snRNP, which is an assembly intermediate of the tri-snRNP. Based on the number of positive cases observed, deleterious variants in RNU4-2 and in RNU6 paralogues could be a significant cause of isolated or dominant RP, accounting for up to 1.2% of all undiagnosed RP cases. This study highlights the role of non-coding genes in rare Mendelian disorders and uncovers pleiotropy in RNU4-2 , where different variants underlie neurodevelopmental disorder and RP. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement C.R. was supported by the Swiss National Science Foundation (SNSF) Grant No. 310030\_204285 entitled Genomics of inherited retinal diseases. S.R. was supported by the Foundation Fighting Blindness Career Development Award (CD-GE-0621-0809-RAD), Radboudumc Starter grant (OZI-23.009) and NWO Aspasia (015.021.028). S.R., C.R., E.D.B., M.B., S.B., D.St., were supported by HORIZON-MSCA-2022-DN (No.101120562, ProgRET). E.D.B., S.R., C.R. were supported by the EJPRD19-234 Solve-RET. This work has been funded by a Foundation Fighting Blindness Program Project Award (PPA-0622 0841-UCL) (to A.J.H, S.R. and S.E.dB.). S.R. and F.P.M.C. were supported by the Gelderse Blindenstichting, the Algemene Nederlandse Vereniging ter voorkoming van Blindheid, Oogfonds, Landelijke Stichting voor Blinden en Slechtzienden, Rotterdamse Stichting Blindenbelangen, Stichting Blindenhulp, Stichting tot Verbetering van het Lot der Blinden, and Stichting Blinden-Penning. M.Q. was supported by the RetinAward 2021. S.H.T. - Jonas Children's Vision Care (JCVC) is supported by the National Institute of Health U01EY030580, U01EY034590 R24EY028758, R24EY027285, 5P30EY019007, R01EY033770, R01EY018213, R01EY024698, the Foundation Fighting Blindness TA-GT-0321-0802-COLU-TRAP, Richard Jaffe, NYEE Foundation, the Rosenbaum Family Foundation, the Gebroe Family Foundation, Piyada Phanaphat Fund, the Research to Prevent Blindness (RPB) Physician-Scientist Award, unrestricted funds from RPB, New York, NY, USA. C.A. was supported by Instituto de Salud Carlos III (ISCIII) of the Ministerio de Ciencia e Innovacion and Union Europea European Regional Development Fund (FEDER) (PI22/00321 and IMP/00009), Centro de Investigacion Biomedica en Red Enfermedades Raras (CIBERER, 06/07/0036), IIS-FJD BioBank (PT13/0010/0012), the Organizacion Nacional de Ciegos Espanoles (ONCE), European Regional Development Fund (FEDER), the University Chair UAM-IIS-FJD of Genomic Medicine. This work was performed by using the data contained in the Programa Infraestructura de Medicina de Precision asociada a la Ciencia y la Tecnologia en Medicina Genomica (IMPaCT-GENoMICA), coordinated by the CIBERER and founded by ISCIII. L.F.C. was supported by Centro de Investigacion Biomedica en Red (CIBER). R.A. was supported by the National Eye Institute (NEI) (RO1 EY030591, RO1 EY031663, T32 EY026590, and P30 EY22589). C.C.W.K was supported by the Combined Ophthalmic Research Rotterdam) grant 8.2.0. S.B. was supported by the Italian Telethon Foundation. G.J.F. and N.C. were supported by Fighting Blindness Ireland (FB22FAR, FB16FAR), Fighting Blindness Ireland - Health Research Charities Ireland (MRCG-2016-14) and Science Foundation Ireland (16/IA/4452 and 22/FFP-A/10544). J.E. was supported by the Macular Society (United Kingdom), and the University of Manchester Core Genomics Technology Facility. T.B.Y. was supported by the Israel Science Foundation (331/24). A.C.B.J. is supported by the University of Melbourne Research Fellowship. K.M.B. was supported by the National Eye Institute (NEI) (RO1 EY035717 and P30 EY014104 [MEE core support]), the Iraty Award 2023, the Lions Foundation, and the Research to Prevent Blindness (Unrestricted Grant). L.S.S., E.L.C. and S.P.D. were supported by grants from the Foundation Fighting Blindness (EGI-GE1218-0753-UCSD) and the Brett & Jane Eberle Foundation. E.D.B. and B.P.L were supported by Ghent University Special Research Fund (BOF20/GOA/023) and E.D.B. (1802220N) and B.P.L. (1803816N) are Senior Clinical Investigators of the Research Foundation-Flanders (FWO). N.M. and S.S. are Ph.D. fellows of HORIZON-MSCA-2022-DN ProgRET (No.101120562). R.A. was supported by the Foundation Fighting Blindness. J.D was supported by the UCSF Vision Core shared resource of the NIH/NEI P30 EY002162, the Foundation Fighting Blindness, and an unrestricted grant from Research to Prevent Blindness. T.I. was supported by research grant from the Japan Agency for Medical Research and Development (AMED) (20ek0109493h0001, 21ek0109493h0002, 22ek0109493h0003, 23ek0109617h0002, 24ek0109617h0003). R.K.K. was supported by The Montreal Children's Hospital Foundation, The Vision Sciences Research Network (VSRN), The National Institutes of Health (NIH)(R01 EY030499-01, Dr. Lentz), The Canadian Institutes for Health Research (CIHR), Fighting Blindness Canada (FBC), and Fonds de Recherche du Quebec - Sante (FRQS). R.K.K. participates in the NAC Attack clinical trial, which is funded by the National Institutes of Health via grants UG1EY033286, UG1EY033293, UG1EY033286, and UG1EY033292. T.M.L., T.L.M and J.N.D.R. were supported by Retina Australia (awarded to the Australian Inherited Retinal Disease Registry and DNA Bank). O.M. was supported by the Wellcome Trust (grant no: 206619/Z/17/Z). T.L.M. was supported by Retina Australia. Awarded to the Australian Inherited Retinal Disease Registry and DNA Bank. M.P. was supported by the BrightFocus Foundation (M2024009N). E.A.P. was supported by the National Eye Institute (NEI) (R01 EY012910). R.R. was supported by Retina South Africa and the South African Medical Research Council (MRC). S.G.S. and E.M.V. were supported by the Italian Ministry of Health (RF-2019-12369368). D.St. was supported by the Ministry of Education, Youth and Sports of the Czech Republic grant for RNA therapy (CZ.02.01.01/00/22\_008/0004575). T.B.H. was supported by the European Commission (Recon4IMD - GAP-101080997) and the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG, grant numbers 418081722 and 433158657 to T.B.H.). P.L. and L.D. were supported by a research grant (NW24-06-00083) from the Ministry of Health of the Czech Republic and UNCE/24/MED/022. V.R.dJ.L.R. and J.C.Z. were supported by the Velux Stiftung Grant 1860. M.A., M.M., C.F.I. J.C.G, A.J.H, and C.T. are supported by Retina UK and Fight for Sight UK (RP Genome Project Grant GR586). A.J.H, J.C.G, M.M, O.A.M, A.W, G.A and S.L were supported by the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology. S.L. was funded by an MRC Clinician Scientist Fellowship. J.M.S. was supported by Instituto de Salud Carlos III (ISCIII) of the Spanish Ministry of Health (PI22/00213), Centro de Investigacion Biomedica en Red Enfermedades Raras (CIBERER, 06/07/1030, CIPROM/2023/26 from the Generalitat Valenciana and IMPaCT-GENOMICA (IMP/00009) co-funded by ISCIII and FEDER. S.R., C.C.W.K, C.J.F.B., A.G. were supported by the Dutch ministry of Education, Culture and Sciences, Gravitation grant: 024.006.034 Lifelong VISION. W.L. was supported by the National Institute of Health/National Eye Institute (1K99EY036930-01). This work is supported by partners of the European Reference Network for Rare Eye Diseases ERN-EYE (Grant Agreement No 101085439, C.J.F.B., E.D.B., C.B.H, S.K, B.P.L, P.L., L.H-W., K.S, L.I.v.d.B.). Novartis contributed funding for the preceding RP-LCA smMIPs panel design and subsequent sequencing (to F.P.M.C., S.R. and D.M.P). Novartis was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Ethikkommission Nordwest- und Zentralschweiz and the Ethics Committee of the Radboud University Medical Center Nijmegen gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Research on the de-identified patient data used in this publication from the Genomics England 100,000 Genomes Project and the NHS GMS dataset can be carried out in the Genomics England Research Environment subject to a collaborative agreement that adheres to patient-led governance. All interested readers will be able to access the data in the same manner that the authors accessed the data. For more information about accessing the data, interested readers may contact research-network{at}genomicsengland.co.uk or access the relevant information on the Genomics England website: <https://www.genomicsengland.co.uk/research>. The data generated during this study (pathogenic variants and VUSs identified) are submitted to the Leiden Open (source) Variation Database (LOVD) (<http://www.lovd.nl>) and ClinVar.

Nature - Valentin Amrhein, Sander Greenland, Blake McShane and more than 800 signatories call for an end to hyped claims and the dismissal of possibly crucial effects.

There is an ethic of believing, and that ethic limits the right to believe when beliefs are false, immoral or dangerous

Transcription is common at active mammalian enhancers sometimes giving rise to stable and unidirectionally transcribed enhancer-associated long intergenic noncoding RNAs (elincRNAs). ElincRNA expression is associated with changes in neighboring gene product abundance and local chromosomal topology, suggesting that transcription at these loci contributes to gene expression regulation in cis . Despite the lack of evidence supporting sequence-dependent functions for most elincRNAs, splicing of these transcripts is unexpectedly common. Whether elincRNA splicing is a mere consequence of their cognate enhancer activity or if it directly impacts enhancer-associated cis -regulation remains unanswered. Here we show that elincRNAs are efficiently and rapidly spliced and that their processing rate is strongly associated with their cognate enhancer activity. This association is supported by: their enrichment in enhancer-specific chromatin signatures; elevated binding of co-transcriptional regulators, including CBP and p300; increased local intra-chromosomal DNA contacts; and strengthened cis -regulation on target gene expression. Using nucleotide polymorphisms at elincRNA splice sites, we found that elincRNA splicing enhances their transcription and directly impacts cis -regulatory function of their cognate enhancers. Importantly, up to 90% of human elincRNAs have nucleotide variants that are associated with both their splicing and the expression levels of their proximal genes. Our results highlight an unexpected contribution of elincRNA splicing to enhancer function.

Biochemists have confirmed the cause of initially unclear symptoms of patients in Israel. Their studies reveal that the patients suffer from a disorder called 'MPS III-E'. It was discovered by the researchers in 2012. However, until now there were no known patients.

Chess changed forever today. And maybe the rest of the world did, too. A little more than a year after AlphaGo sensationally won against the top Go player, the artificial-intelligence program AlphaZero has obliterated the highest-rated chess engine. Stockfish, which for most top players is their go-to...

Studies of host genetic determinants of pathogen sequence variation can identify sites of genomic conflicts, by highlighting variants that are implicated in immune response on the host side and adaptive escape on the pathogen side. However, systematic genetic differences in host and pathogen populations can lead to inflated type I (false positive) and type II (false negative) error rates in genome-wide association analyses. Here, we demonstrate through simulation that correcting for both host and pathogen stratification reduces spurious signals and increases power to detect real associations in a variety of tested scenarios. We confirm the validity of the simulations by showing comparable results in an analysis of paired human and HIV genomes.

Hereditary retinal degenerations (HRDs) are rare diseases leading to progressive visual impairment and blindness. They are generally transmitted as monogenic traits, obeying Mendel’s laws of inheritance, and affect indiscriminately individuals from all ethnic groups. However, compared to other populations, Japanese display a unique landscape of HRD mutations. Following the genomic screening of 331 unrelated Japanese patients, we identified two alleles in the ciliary gene RP1 that were enriched in patients but were also relatively prevalent in the general population. The first was determined by the insertion of an Alu element in the coding sequence of the gene (allele frequency in the Japanese population = 0.1%), while the other was a nonsense variant in the same exon (p.Arg1933*). This latter nonsense was found to be almost polymorphic in Japan (allele frequency = 0.6%), did not cause disease in homozygosis or heterozygosis, but was considerably enriched in HRD patients (allele frequency = 2.1%, i.e. a 3.5-fold enrichment; p -value = 1.29x10-6). Interestingly, family and population analyses showed that p.Arg1933* could act as a Mendelian mutation, in trans with other pathogenic variants, but also cause disease in conjunction with hypomorphic or recessive alleles in ciliary genes elsewhere in the genome, according to an oligogenic pattern of inheritance. Our data corroborate the model of mutational load for ciliopathy, not only for a selected group of families, but at a population-wide level. In addition, our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model that could fill the gap that currently exists between monogenic and complex diseases.