Dr. Arno’s research is broadly focused on the elucidation and characterization of genetic defects that lead to rare disease. Over the past 12 years, his laboratory has made significant advances in the field of ophthalmic genetics and genomic analysis of inherited eye disease (IED). This has included pioneering the use of whole genome sequencing (WGS) for inherited retinal disease (IRD) genetic analysis as part of the UK’s National Institute for Health Research (NIHR) Bioresource study and the 100,000 Genomes Project. Dr. Arno has led several novel IRD gene discovery projects including REEP6 in retinitis pigmentosa, ARHGEF18 in retinal degeneration, SSBP1 in autosomal dominant optic atrophy and CFAP20 in syndromic and non-syndromic retinitis pigmentosa.
In his role as Associate Director of Research (Innovation), Dr. Arno works in collaboration with the faculty team and divisions across the GGC to advance our understanding of the impact of rare genetic variation on disease. His laboratory uses advanced variant interrogation methods to characterize WGS identified genomic variants, downstream functional investigations of variants and genes of uncertain significance, long-read sequencing including genome-wide and targeted Oxford Nanopore Technologies sequencing for genetic analysis and developing new methods of investigation to improve diagnostic rates and patient outcomes.
Dr. Arno is also honorary Associate Professor at the Institute of Ophthalmology, University College London, UK, honorary Principle Investigator at the Laboratory of Visual Physiology/Ophthalmic Genetics, National Institute of Sensory Organs, Tokyo, Japan, co-chair of the Clinical Genome Resource (ClinGen, https://clinicalgenome.org/) Retina Gene Curation Expert Panel (GCEP) and co-lead of the Genomics England Genotype-Phenotype Association Community (https://www.genomicsengland.co.uk/research-network-communities?chapter=genotype-phenotype-association-community).
Advancing our understanding of novel genes and non-coding variants in inherited disease
Within the paradigm of IRD and beyond, we perform advanced variant interrogation pipelines on patient WGS data. This includes structural and non-coding variant analysis and gene agnostic pipelines to identify the missing heritability in IRD, multi-disciplinary team variant classification, novel variant investigations including splice analysis, regulatory impact studies, resolution of complex rearrangements, and wet-lab functional studies of candidate variants and genes with RNA-seq, RT-PCR, Luciferase gene reporter assays and long-read sequencing to resolve variants of uncertain significance and characterize novel genetic disease mechanisms.
Investigating the clinical utility of Oxford Nanopore Technologies Long-Read Sequencing for variants, genotypes and genetic loci intractable to short-read NGS
The objective is to develop long-read based approaches to investigate genetic variants in patient DNA samples for the improvement of diagnostic workflows. Many genes and genomic regions are poorly sequenced using short-read technology due to low complexity or repetitive regions etc. In addition, structural variants are often poorly detected or defined with traditional methods and many genotypes cannot be fully resolved without access to family (parental) segregation analysis and phasing. We use long-read sequencing, including genome-wide and targeted sequencing to investigate genomic regions and specific diagnostic questions, working with the directors across the center and applying this cutting edge technology for direct patient benefit in addition to advancing our knowledge of rare disease genetics.
Selected Publications
- Varela MD, Bellingham J, Motta F, Jurkute N, Ellingford JM, Quinodoz M, Oprych K, Niblock M, Janeschitz-Kriegl L, Kaminska K, Cancellieri F, Scholl HPN, Lenassi E, Schiff E, Knight H, Black G, Rivolta C, Cheetham ME, Michaelides M, Mahroo OA, Moore AT, Webster AR, Arno G. Multi-disciplinary team directed analysis of whole genome sequencing reveals pathogenic non-coding variants in molecularly undiagnosed inherited retinal dystrophies. Hum Mol Genet 2023 Jan 27;32(4):595-607. (https://pubmed.ncbi.nlm.nih.gov/36084042/)
- Chrystal PW, Lambacher NJ, Doucette LP, Bellingham J, Schiff ER, Noel NCL, Li C, Tsiropoulou S, Casey GA, Zhai Y, Nadolski NJ, Majumder MH, Tagoe J, D’Esposito F, Cordeiro MF, Downes S, Clayton-Smith J, Ellingford J; Genomics England Research Consortium; Mahroo OA, Hocking JC, Cheetham ME, Webster AR, Jansen G, Blacque OE, Allison WT*, Au PYB*, MacDonald IM*, Arno G*, Leroux MR*. Nat Commun. 2022 Nov 3;13(1):6595. (https://pubmed.ncbi.nlm.nih.gov/36329026/)
- The 100,000 Genomes Project Pilot Investigators. (Joint first author). 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care – Preliminary Report. N Engl J Med. 2021 Nov 11;385(20):1868-1880. (https://pubmed.ncbi.nlm.nih.gov/34758253/)
- Carss KJ*, Arno G*, Erwood M, Stephens J, Sanchis-Juan A, Hull S, Megy K, Grozeva D, Dewhurst E, Malka S, Plagnol V, Penkett C, Stirrups K, Rizzo R, Wright G, Josifova D, Bitner-Glindzicz M, Scott RH, Clement E, Allen L, Armstrong R, Brady AF, Carmichael J, Chitre M, Henderson RH, Hurst J, MacLaren RE, Murphy E, Paterson J, Rosser E, Thompson DA, Wakeling E, Ouwehand WH, Michaelides M, Moore AT; NIHR-BioResource Rare Diseases Consortium., Webster AR, Raymond FL. Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease. Am J Hum Genet. 2017 Jan 5;100(1):75-90. (https://pubmed.ncbi.nlm.nih.gov/28041643/)
