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1. The landscape of submicroscopic structural variants at the OPN1LW/OPN1MW gene cluster on Xq28 underlying blue cone monochromacy

Author

Wissinger B, Baumann B, Buena-Atienza E, Ravesh Z, Cideciyan AV, Stingl K, Audo I, Meunier I, Bocquet B, Traboulsi EI, Hardcastle AJ, Gardner JC, Michaelides M, Branham KE, Rosenberg T, Andreasson S, Dollfus H, Birch D, Vincent AL, Martorell-Sampol L, Catala J, Kellner U, Rüther K, Lorenz B, Preising MN, Manfredini E, Zarate YA, Vijzelaar R, Zrenner E, Jacobson SG, and Kohl S

Subjects
gene conversion, BCM, human visual pigment genes, opsin gene deletion, locus control region
Abstract

Blue cone monochromacy (BCM) is an X-linked retinal disorder characterized by low vision, photoaversion, and poor color discrimination. BCM is due to the lack of long-wavelength-sensitive and middle-wavelength-sensitive cone photoreceptor function and caused by mutations in the OPN1LW/OPN1MW gene cluster on Xq28. Here, we investigated the prevalence and the landscape of submicroscopic structural variants (SVs) at single-base resolution in BCM patients. We found that about one-third (n = 73) of the 213 molecularly confirmed BCM families carry an SV, most commonly deletions restricted to the OPN1LW/OPN1MW gene cluster. The structure and precise breakpoints of the SVs were resolved in all but one of the 73 families. Twenty-two families-all from the United States-showed the same SV, and we confirmed a common ancestry of this mutation. In total, 42 distinct SVs were identified, including 40 previously unreported SVs, thereby quadrupling the number of precisely mapped SVs underlying BCM. Notably, there was no "region of overlap" among these SVs. However, 90% of SVs encompass the upstream locus control region, an essential enhancer element. Its minimal functional extent based on deletion mapping in patients was refined to 358 bp. Breakpoint analyses suggest diverse mechanisms underlying SV formation as well as in one case the gene conversion-based exchange of a 142-bp deletion between opsin genes. Using parsimonious assumptions, we reconstructed the composition and copy number of the OPN1LW/OPN1MW gene cluster prior to the mutation event and found evidence that large gene arrays may be predisposed to the occurrence of SVs at this locus.

Published
2022

2. Pathway Analysis Integrating Genome-Wide and Functional Data Identifies PLCG2 as a Candidate Gene for Age-Related Macular Degeneration

Author

Waksmunski, AR, Grunin, M, Kinzy, TG, Igo, RP, Haines, JL, Bailey, JNC, Fritsche, LG, Igl, W, Grassmann, F, Sengupta, S, Bragg-Gresham, JL, Burdon, KP, Hebbring, SJ, Wen, C, Gorski, M, Kim, IK, Cho, D, Zack, D, Souied, E, Scholl, HPN, Bala, E, Lee, KE, Hunter, DJ, Sardell, RJ, Mitchell, P, Merriam, JE, Cipriani, V, Hoffman, JD, Schick, T, Lechanteur, YTE, Guymer, RH, Johnson, MP, Jiang, Y, Stanton, CM, Buitendijk, GHS, Zhan, X, Kwong, AM, Boleda, A, Brooks, M, Gieser, L, Ratnapriya, R, Branham, KE, Foerster, JR, Heckenlively, JR, Othman, M, Vote, BJ, Liang, HH, Souzeau, E, McAllister, IL, Isaacs, T, Hall, J, Lake, S, Mackey, DA, Constable, IJ, Craig, JE, Kitchner, TE, Yang, Z, Su, Z, Luo, H, Chen, D, Ouyang, H, Flagg, K, Lin, D, Mao, G, Ferreyra, H, Stark, K, von Strachwitz, CN, Wolf, A, Brandl, C, Rudolph, G, Olden, M, Morrison, MA, Morgan, DJ, Schu, M, Ahn, J, Silvestri, G, Tsironi, EE, Park, KH, Farrer, LA, Orlin, A, Brucker, A, Li, M, Curcio, CA, Mohand-Said, S, Sahel, J-A, Audo, I, Benchaboune, M, Cree, AJ, Rennie, CA, Goverdhan, S, Hagbi-Levi, S, Campochiaro, P, Katsanis, N, Holz, FG, Blond, F, Blanche, H, Deleuze, J-F, Truitt, B, Peachey, NS, Meuer, SM, Myers, CE, Moore, EL, Klein, R, Hauser, MA, Postel, EA, Courtenay, MD, Schwartz, SG, Kovach, JL, Scott, WK, Liew, G, Tan, AG, Gopinath, B, Merriam, JC, Smith, RT, Khan, JC, Shahid, H, Moore, AT, McGrath, JA, Laux, R, Brantley, MA, Agarwal, A, Ersoy, L, Caramoy, A, Langmann, T, Saksens, NTM, de Jong, EK, Hoyng, CB, Cain, MS, Richardson, AJ, Martin, TM, Blangero, J, Weeks, DE, Dhillon, B, van Duijn, CM, Doheny, KF, Romm, J, Klaver, CCW, Hayward, C, Gorin, MB, Klein, ML, Baird, PN, den Hollander, A, Fauser, S, Yates, JRW, Allikmets, R, Wang, JJ, Schaumberg, DA, Klein, BEK, Hagstrom, SA, Chowers, I, Lotery, AJ, Leveillard, T, Zhang, K, Brilliant, MH, Hewitt, AW, Swaroop, A, Chew, EY, Pericak-Vance, MA, DeAngelis, M, Stambolian, D, Iyengar, SK, Weber, BHF, Abecasis, GR, Heid, IM, Waksmunski, AR, Grunin, M, Kinzy, TG, Igo, RP, Haines, JL, Bailey, JNC, Fritsche, LG, Igl, W, Grassmann, F, Sengupta, S, Bragg-Gresham, JL, Burdon, KP, Hebbring, SJ, Wen, C, Gorski, M, Kim, IK, Cho, D, Zack, D, Souied, E, Scholl, HPN, Bala, E, Lee, KE, Hunter, DJ, Sardell, RJ, Mitchell, P, Merriam, JE, Cipriani, V, Hoffman, JD, Schick, T, Lechanteur, YTE, Guymer, RH, Johnson, MP, Jiang, Y, Stanton, CM, Buitendijk, GHS, Zhan, X, Kwong, AM, Boleda, A, Brooks, M, Gieser, L, Ratnapriya, R, Branham, KE, Foerster, JR, Heckenlively, JR, Othman, M, Vote, BJ, Liang, HH, Souzeau, E, McAllister, IL, Isaacs, T, Hall, J, Lake, S, Mackey, DA, Constable, IJ, Craig, JE, Kitchner, TE, Yang, Z, Su, Z, Luo, H, Chen, D, Ouyang, H, Flagg, K, Lin, D, Mao, G, Ferreyra, H, Stark, K, von Strachwitz, CN, Wolf, A, Brandl, C, Rudolph, G, Olden, M, Morrison, MA, Morgan, DJ, Schu, M, Ahn, J, Silvestri, G, Tsironi, EE, Park, KH, Farrer, LA, Orlin, A, Brucker, A, Li, M, Curcio, CA, Mohand-Said, S, Sahel, J-A, Audo, I, Benchaboune, M, Cree, AJ, Rennie, CA, Goverdhan, S, Hagbi-Levi, S, Campochiaro, P, Katsanis, N, Holz, FG, Blond, F, Blanche, H, Deleuze, J-F, Truitt, B, Peachey, NS, Meuer, SM, Myers, CE, Moore, EL, Klein, R, Hauser, MA, Postel, EA, Courtenay, MD, Schwartz, SG, Kovach, JL, Scott, WK, Liew, G, Tan, AG, Gopinath, B, Merriam, JC, Smith, RT, Khan, JC, Shahid, H, Moore, AT, McGrath, JA, Laux, R, Brantley, MA, Agarwal, A, Ersoy, L, Caramoy, A, Langmann, T, Saksens, NTM, de Jong, EK, Hoyng, CB, Cain, MS, Richardson, AJ, Martin, TM, Blangero, J, Weeks, DE, Dhillon, B, van Duijn, CM, Doheny, KF, Romm, J, Klaver, CCW, Hayward, C, Gorin, MB, Klein, ML, Baird, PN, den Hollander, A, Fauser, S, Yates, JRW, Allikmets, R, Wang, JJ, Schaumberg, DA, Klein, BEK, Hagstrom, SA, Chowers, I, Lotery, AJ, Leveillard, T, Zhang, K, Brilliant, MH, Hewitt, AW, Swaroop, A, Chew, EY, Pericak-Vance, MA, DeAngelis, M, Stambolian, D, Iyengar, SK, Weber, BHF, Abecasis, GR, and Heid, IM

Abstract

PURPOSE: Age-related macular degeneration (AMD) is the worldwide leading cause of blindness among the elderly. Although genome-wide association studies (GWAS) have identified AMD risk variants, their roles in disease etiology are not well-characterized, and they only explain a portion of AMD heritability. METHODS: We performed pathway analyses using summary statistics from the International AMD Genomics Consortium's 2016 GWAS and multiple pathway databases to identify biological pathways wherein genetic association signals for AMD may be aggregating. We determined which genes contributed most to significant pathway signals across the databases. We characterized these genes by constructing protein-protein interaction networks and performing motif analysis. RESULTS: We determined that eight genes (C2, C3, LIPC, MICA, NOTCH4, PLCG2, PPARA, and RAD51B) "drive" the statistical signals observed across pathways curated in the Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, and Gene Ontology (GO) databases. We further refined our definition of statistical driver gene to identify PLCG2 as a candidate gene for AMD due to its significant gene-level signals (P < 0.0001) across KEGG, Reactome, GO, and NetPath pathways. CONCLUSIONS: We performed pathway analyses on the largest available collection of advanced AMD cases and controls in the world. Eight genes strongly contributed to significant pathways from the three larger databases, and one gene (PLCG2) was central to significant pathways from all four databases. This is, to our knowledge, the first study to identify PLCG2 as a candidate gene for AMD based solely on genetic burden. Our findings reinforce the utility of integrating in silico genetic and biological pathway data to investigate the genetic architecture of AMD.

Published
2019

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

Author

Fritsche, LG, Igl, W, Bailey, JNC, Grassmann, F, Sengupta, S, Bragg-Gresham, JL, Burdon, KP, Hebbring, SJ, Wen, C, Gorski, M, Kim, IK, Cho, D, Zack, D, Souied, E, Scholl, HPN, Bala, E, Lee, KE, Hunter, DJ, Sardell, RJ, Mitchell, P, Merriam, JE, Cipriani, V, Hoffman, JD, Schick, T, Lechanteur, YTE, Guymer, RH, Johnson, MP, Jiang, Y, Stanton, CM, Buitendijk, GHS, Zhan, X, Kwong, AM, Boleda, A, Brooks, M, Gieser, L, Ratnapriya, R, Branham, KE, Foerster, JR, Heckenlively, JR, Othman, MI, Vote, BJ, Liang, HH, Souzeau, E, McAllister, IL, Isaacs, T, Hall, J, Lake, S, Mackey, DA, Constable, IJ, Craig, JE, Kitchner, TE, Yang, Z, Su, Z, Luo, H, Chen, D, Hong, O, Flagg, K, Lin, D, Mao, G, Ferreyra, H, Starke, K, von Strachwitz, CN, Wolf, A, Brandl, C, Rudolph, G, Olden, M, Morrison, MA, Morgan, DJ, Schu, M, Ahn, J, Silvestri, G, Tsironi, EE, Park, KH, Farrer, LA, Orlin, A, Brucker, A, Li, M, Curcio, CA, Mohand-Said, S, Sahel, J-M, Audo, I, Benchaboune, M, Cree, AJ, Rennie, CA, Goverdhan, SV, Grunin, M, Hagbi-Levi, S, Campochiaro, P, Katsanis, N, Holz, FG, Blond, F, Blanche, H, Deleuze, J-F, Igo, RP, Truitt, B, Peachey, NS, Meuer, SM, Myers, CE, Moore, EL, Klein, R, Hauser, MA, Postel, EA, Courtenay, MD, Schwartz, SG, Kovach, JL, Scott, WK, Liew, G, Tan, AG, Gopinath, B, Merriam, JC, Smith, RT, Khan, JC, Shahid, H, Moore, AT, McGrath, JA, Laux, R, Brantley, MA, Agarwal, A, Ersoy, L, Caramoy, A, Langmann, T, Saksens, NTM, de Jong, EK, Hoyng, CB, Cain, MS, Richardson, AJ, Martin, TM, Blangero, J, Weeks, DE, Dhillon, B, van Duijn, CM, Doheny, KF, Romm, J, Klaver, CCW, Hayward, C, Gorin, MB, Klein, ML, Baird, PN, den Hollander, AI, Fauser, S, Yates, JRW, Allikmets, R, Wang, JJ, Schaumberg, DA, Klein, BEK, Hagstrom, SA, Chowers, I, Lotery, AJ, Leveillard, T, Zhang, K, Brilliant, MH, Hewitt, AW, Swaroop, A, Chew, EY, Pericak-Vance, MA, DeAngelis, M, Stambolian, D, Haines, JL, Iyengar, SK, Weber, BHF, Abecasis, GR, Heid, IM, Fritsche, LG, Igl, W, Bailey, JNC, Grassmann, F, Sengupta, S, Bragg-Gresham, JL, Burdon, KP, Hebbring, SJ, Wen, C, Gorski, M, Kim, IK, Cho, D, Zack, D, Souied, E, Scholl, HPN, Bala, E, Lee, KE, Hunter, DJ, Sardell, RJ, Mitchell, P, Merriam, JE, Cipriani, V, Hoffman, JD, Schick, T, Lechanteur, YTE, Guymer, RH, Johnson, MP, Jiang, Y, Stanton, CM, Buitendijk, GHS, Zhan, X, Kwong, AM, Boleda, A, Brooks, M, Gieser, L, Ratnapriya, R, Branham, KE, Foerster, JR, Heckenlively, JR, Othman, MI, Vote, BJ, Liang, HH, Souzeau, E, McAllister, IL, Isaacs, T, Hall, J, Lake, S, Mackey, DA, Constable, IJ, Craig, JE, Kitchner, TE, Yang, Z, Su, Z, Luo, H, Chen, D, Hong, O, Flagg, K, Lin, D, Mao, G, Ferreyra, H, Starke, K, von Strachwitz, CN, Wolf, A, Brandl, C, Rudolph, G, Olden, M, Morrison, MA, Morgan, DJ, Schu, M, Ahn, J, Silvestri, G, Tsironi, EE, Park, KH, Farrer, LA, Orlin, A, Brucker, A, Li, M, Curcio, CA, Mohand-Said, S, Sahel, J-M, Audo, I, Benchaboune, M, Cree, AJ, Rennie, CA, Goverdhan, SV, Grunin, M, Hagbi-Levi, S, Campochiaro, P, Katsanis, N, Holz, FG, Blond, F, Blanche, H, Deleuze, J-F, Igo, RP, Truitt, B, Peachey, NS, Meuer, SM, Myers, CE, Moore, EL, Klein, R, Hauser, MA, Postel, EA, Courtenay, MD, Schwartz, SG, Kovach, JL, Scott, WK, Liew, G, Tan, AG, Gopinath, B, Merriam, JC, Smith, RT, Khan, JC, Shahid, H, Moore, AT, McGrath, JA, Laux, R, Brantley, MA, Agarwal, A, Ersoy, L, Caramoy, A, Langmann, T, Saksens, NTM, de Jong, EK, Hoyng, CB, Cain, MS, Richardson, AJ, Martin, TM, Blangero, J, Weeks, DE, Dhillon, B, van Duijn, CM, Doheny, KF, Romm, J, Klaver, CCW, Hayward, C, Gorin, MB, Klein, ML, Baird, PN, den Hollander, AI, Fauser, S, Yates, JRW, Allikmets, R, Wang, JJ, Schaumberg, DA, Klein, BEK, Hagstrom, SA, Chowers, I, Lotery, AJ, Leveillard, T, Zhang, K, Brilliant, MH, Hewitt, AW, Swaroop, A, Chew, EY, Pericak-Vance, MA, DeAngelis, M, Stambolian, D, Haines, JL, Iyengar, SK, Weber, BHF, Abecasis, GR, and Heid, IM

Abstract

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

Published
2016

4. Whole genome sequencing of 4,787 individuals identifies gene-based rare variants in age-related macular degeneration.

Author

Kwong A, Zawistowski M, Fritsche LG, Zhan X, Bragg-Gresham J, Branham KE, Advani J, Othman M, Ratnapriya R, Teslovich TM, Stambolian D, Chew EY, Abecasis GR, and Swaroop A

Subjects
Humans, Genotype, Genetic Testing, Whole Genome Sequencing, Polymorphism, Single Nucleotide genetics, Genetic Predisposition to Disease, Complement Factor H genetics, Genome-Wide Association Study methods, Macular Degeneration genetics
Abstract

Genome-wide association studies have contributed extensively to the discovery of disease-associated common variants. However, the genetic contribution to complex traits is still largely difficult to interpret. We report a genome-wide association study of 2394 cases and 2393 controls for age-related macular degeneration (AMD) via whole-genome sequencing, with 46.9 million genetic variants. Our study reveals significant single-variant association signals at four loci and independent gene-based signals in CFH, C2, C3, and NRTN. Using data from the Exome Aggregation Consortium (ExAC) for a gene-based test, we demonstrate an enrichment of predicted rare loss-of-function variants in CFH, CFI, and an as-yet unreported gene in AMD, ORMDL2. Our method of using a large variant list without individual-level genotypes as an external reference provides a flexible and convenient approach to leverage the publicly available variant datasets to augment the search for rare variant associations, which can explain additional disease risk in AMD., (© Published by Oxford University Press 2023.)

Published
2024
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5. Characterization of the Spectrum of Ophthalmic Changes in Patients With Alagille Syndrome.

Author

da Palma MM, Igelman AD, Ku C, Burr A, You JY, Place EM, Wang NK, Oh JK, Branham KE, Zhang X, Ahn J, Gorin MB, Lam BL, Ronquillo CC, Bernstein PS, Nagiel A, Huckfeldt R, Cabrera MT, Kelly JP, Bakall B, Iannaccone A, Hufnagel RB, Zein WM, Koenekoop RK, Birch DG, Yang P, Fahim AT, and Pennesi ME

Subjects
Adult, Alagille Syndrome genetics, Alagille Syndrome physiopathology, Diagnosis, Differential, Female, Fluorescein Angiography methods, Genetic Testing methods, Humans, Jagged-1 Protein genetics, Male, Medical Records, Mutation, Optical Imaging methods, Tomography, Optical Coherence methods, Visual Acuity, Visual Field Tests methods, Alagille Syndrome diagnosis, Eye Diseases, Hereditary diagnosis, Eye Diseases, Hereditary physiopathology, Optic Disk abnormalities, Optic Disk diagnostic imaging, Retina abnormalities, Retina diagnostic imaging
Abstract

Purpose: The purpose of this study was to characterize the phenotypic spectrum of ophthalmic findings in patients with Alagille syndrome., Methods: We conducted a retrospective, observational, multicenter, study on 46 eyes of 23 subjects with Alagille syndrome. We reviewed systemic and ophthalmologic data extracted from medical records, color fundus photography, fundus autofluorescence, optical coherence tomography, visual fields, electrophysiological assessments, and molecular genetic findings., Results: Cardiovascular abnormalities were found in 83% of all cases (of those, 74% had cardiac murmur), whereas 61% had a positive history of hepatobiliary issues, and musculoskeletal anomalies were present in 61% of all patients. Dysmorphic facies were present in 16 patients, with a broad forehead being the most frequent feature. Ocular symptoms were found in 91%, with peripheral vision loss being the most frequent complaint. Median (range) Snellen visual acuity of all eyes was 20/25 (20/20 to hand motion [HM]). Anterior segment abnormalities were present in 74% of the patients; of those, posterior embryotoxon was the most frequent finding. Abnormalities of the optic disc were found in 52%, and peripheral retinal abnormalities were the most frequent ocular finding in this series, found in 96% of all patients. Fifteen JAG1 mutations were identified in 16 individuals; of those, 6 were novel., Conclusions: This study reports a cohort of patients with Alagille syndrome in which peripheral chorioretinal changes were more frequent than posterior embryotoxon, the most frequent ocular finding according to a number of previous studies. We propose that these peripheral chorioretinal changes are a new hallmark to help diagnose this syndrome.

Published
2021
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6. Advancing Clinical Trials for Inherited Retinal Diseases: Recommendations from the Second Monaciano Symposium.

Author

Thompson DA, Iannaccone A, Ali RR, Arshavsky VY, Audo I, Bainbridge JWB, Besirli CG, Birch DG, Branham KE, Cideciyan AV, Daiger SP, Dalkara D, Duncan JL, Fahim AT, Flannery JG, Gattegna R, Heckenlively JR, Heon E, Jayasundera KT, Khan NW, Klassen H, Leroy BP, Molday RS, Musch DC, Pennesi ME, Petersen-Jones SM, Pierce EA, Rao RC, Reh TA, Sahel JA, Sharon D, Sieving PA, Strettoi E, Yang P, and Zacks DN

Subjects
Humans, Precision Medicine, Retina, Retinal Diseases drug therapy
Abstract

Major advances in the study of inherited retinal diseases (IRDs) have placed efforts to develop treatments for these blinding conditions at the forefront of the emerging field of precision medicine. As a result, the growth of clinical trials for IRDs has increased rapidly over the past decade and is expected to further accelerate as more therapeutic possibilities emerge and qualified participants are identified. Although guided by established principles, these specialized trials, requiring analysis of novel outcome measures and endpoints in small patient populations, present multiple challenges relative to study design and ethical considerations. This position paper reviews recent accomplishments and existing challenges in clinical trials for IRDs and presents a set of recommendations aimed at rapidly advancing future progress. The goal is to stimulate discussions among researchers, funding agencies, industry, and policy makers that will further the design, conduct, and analysis of clinical trials needed to accelerate the approval of effective treatments for IRDs, while promoting advocacy and ensuring patient safety., Competing Interests: Disclosure: D.A. Thompson, MeiraGTx (F), filed patent on gene therapy (P); A. Iannaccone, Editas Medicine (C), Astellas (C), Roivant Pharma (C), IQVIA (C), Gyroscope/Orbit Biomedical (C), Rhythm Pharmaceuticals (C), Applied Genetic Technologies Corp (F), Allergan (F), Acucela (F), ProQR Therapeutics (F), Foundation Fighting Blindness Clinical Research Institute (F), Alia Therapeutics (S); R.R. Ali, MeiraGTx (S), filed patents on gene and cell therapies (P); V.Y. Arshavsky, None; I. Audo, None; J.W.B. Bainbridge, MeiraGTx (S), filed patents on gene and cell therapies (P); C.G. Besirli, MeiraGTx (F), Spark Therapeutics (F); D.G. Birch, Nightstar Therapeutics/Biogen (C), Applied Genetic Technologies Corp (S), Nacuity Pharmaceuticals (C), Editas Medicine (C), Acucela (S), Foundation Fighting Blindness (C), ProQR Therapeutics (C); K.E. Branham, ProQR Therapeutics (C); A.V. Cideciyan, Patents on gene therapies for RPGR, RHO, and NPHP5-associated IRDs (P); ProQR Therapeutics (F), IVERIC bio (F); S.P. Daiger, Applied Genetic Technologies Corp (S); D. Dalkara, Patent on AAV virions with variant capsid and methods of use (P); J.L. Duncan, 4D Therapeutics (C), Applied Genetic Technologies Corp (C), Editas Medicine (C), Gyroscope (C), Horama (C), Nightstar Therapeutics/Biogen (C), ProQR Therapeutics (C), SparingVision (S), Spark Therapeutics (C), Vedere Bio (C), Acucela (F), Allergan (F), Neurotech (F), Second Sight Medical Products (F); A.T. Fahim, None; J.G. Flannery, None; R. Gattegna, None; J.R. Heckenlively, None; E. Heon, None; K.T. Jayasundera, Editas Medicine (C); N.W. Khan, None; H. Klassen, jCyte (S, I); B.P. Leroy, Bayer (C), Nightstar Therapeutics/Biogen (C), IVERIC bio (C), Novartis Pharma (C), RegenX Bio (C), Vedere Bio (C); Novartis (R), Spark Therapeutics (R); GenSight Biologics (F), ProQR Therapeutics (F); R.S. Molday, Applied Genetic Technologies Corp (S); D.C. Musch, Belite Bio (S), Mactel Group NTMT-03 trial (S), NEI intramural branch clinical trials (S); M.E. Pennesi, Adverum (C), Allergan (C), Astellas (C), Pharmaceuticals (C), Biogen (C), IVERIC bio (C), Novartis (C), Regenix Bio (C), Spark Therapeutics (C), Wave Biosciences (C), Eyevensys (S), Horama (S), Nayan (S), Nacuity Pharmaceuticals (S, I), Ocugen (S, I), Verede (S), ProQR Therapeutics (S), Gensight (S), Applied Genetic Technologies Corp (F), Sanofi (F), Foundation Fighting Blindness (F), ProQR Therapeutics (F), Allergan (F); S.M. Petersen-Jones, None; E.A. Pierce, Astellas (C), Merck (C), Sanofi-Genzyme (C), Wave Therapeutics (C); GenSight Biologics (S), Odylia Therapeutics (S), Opsis Therapeutics (S), Sana Biotechnology (S); CRISPR Therapeutics (F), Spark Therapeutics (F); Editas Medicine (F), MeiraGTx (F), ProQR Therapeutics (F), filed patents on gene and genetic therapies (P); R.C. Rao, None; T.A. Reh, Nayan Pharmaceuticals (C, I); J.A. Sahel, Pixium Vision (S, I), GenSight Biologics (S, I), SparingVision (S, I); Prophesee (I), Chronolife (I); D. Sharon, None; P.A. Sieving, None; E. Strettoi, None; P. Yang, Astellas (C), Applied Genetic Technologies Corp (C); D.N. Zacks, ONL Therapeutics (C, I, P), (Copyright 2020 The Authors.)

Published
2020
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7. Contribution of noncoding pathogenic variants to RPGRIP1-mediated inherited retinal degeneration.

Author

Jamshidi F, Place EM, Mehrotra S, Navarro-Gomez D, Maher M, Branham KE, Valkanas E, Cherry TJ, Lek M, MacArthur D, Pierce EA, and Bujakowska KM

Subjects
Adult, Chromosome Mapping, Cytoskeletal Proteins, DNA Mutational Analysis methods, DNA, Intergenic physiology, Female, HEK293 Cells, Humans, Male, Mutation, Pedigree, Proteins physiology, Retinal Degeneration etiology, Exome Sequencing methods, Whole Genome Sequencing methods, DNA, Intergenic genetics, Proteins genetics, Retinal Degeneration genetics
Abstract

Purpose: With the advent of gene therapies for inherited retinal degenerations (IRDs), genetic diagnostics will have an increasing role in clinical decision-making. Yet the genetic cause of disease cannot be identified using exon-based sequencing for a significant portion of patients. We hypothesized that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and evaluated patients with single coding pathogenic variants in RPGRIP1 to test this hypothesis., Methods: IRD families underwent targeted panel sequencing. Unsolved cases were explored by exome and genome sequencing looking for additional pathogenic variants. Candidate pathogenic variants were then validated by Sanger sequencing, quantitative polymerase chain reaction, and in vitro splicing assays in two cell lines analyzed through amplicon sequencing., Results: Among 1722 families, 3 had biallelic loss-of-function pathogenic variants in RPGRIP1 while 7 had a single disruptive coding pathogenic variants. Exome and genome sequencing revealed potential noncoding pathogenic variants in these 7 families. In 6, the noncoding pathogenic variants were shown to lead to loss of function in vitro., Conclusion: Noncoding pathogenic variants were identified in 6 of 7 families with single coding pathogenic variants in RPGRIP1. The results suggest that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and RPGRIP1-mediated IRDs are more common than previously thought.

Published
2019
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8. A Novel Dominant Mutation in SAG, the Arrestin-1 Gene, Is a Common Cause of Retinitis Pigmentosa in Hispanic Families in the Southwestern United States.

Author

Sullivan LS, Bowne SJ, Koboldt DC, Cadena EL, Heckenlively JR, Branham KE, Wheaton DH, Jones KD, Ruiz RS, Pennesi ME, Yang P, Davis-Boozer D, Northrup H, Gurevich VV, Chen R, Xu M, Li Y, Birch DG, and Daiger SP

Subjects
Adult, Aged, DNA Mutational Analysis, Exons genetics, Female, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Pedigree, Retina physiopathology, Retinitis Pigmentosa diagnosis, Retinitis Pigmentosa physiopathology, Southwestern United States, Arrestin genetics, Genes, Dominant, Hispanic or Latino genetics, Mutation, Missense, Retinitis Pigmentosa genetics
Abstract

Purpose: To identify the causes of autosomal dominant retinitis pigmentosa (adRP) in a cohort of families without mutations in known adRP genes and consequently to characterize a novel dominant-acting missense mutation in SAG., Methods: Patients underwent ophthalmologic testing and were screened for mutations using targeted-capture and whole-exome next-generation sequencing. Confirmation and additional screening were done by Sanger sequencing. Haplotypes segregating with the mutation were determined using short tandem repeat and single nucleotide variant polymorphisms. Genealogies were established by interviews of family members., Results: Eight families in a cohort of 300 adRP families, and four additional families, were found to have a novel heterozygous mutation in the SAG gene, c.440G>T; p.Cys147Phe. Patients exhibited symptoms of retinitis pigmentosa and none showed symptoms characteristic of Oguchi disease. All families are of Hispanic descent and most were ascertained in Texas or California. A single haplotype including the SAG mutation was identified in all families. The mutation dramatically alters a conserved amino acid, is extremely rare in global databases, and was not found in 4000+ exomes from Hispanic controls. Molecular modeling based on the crystal structure of bovine arrestin-1 predicts protein misfolding/instability., Conclusions: This is the first dominant-acting mutation identified in SAG, a founder mutation possibly originating in Mexico several centuries ago. The phenotype is clearly adRP and is distinct from the previously reported phenotypes of recessive null mutations, that is, Oguchi disease and recessive RP. The mutation accounts for 3% of the 300 families in the adRP Cohort and 36% of Hispanic families in this cohort.

Published
2017
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9. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

Author

Fritsche LG, Igl W, Bailey JN, Grassmann F, Sengupta S, Bragg-Gresham JL, Burdon KP, Hebbring SJ, Wen C, Gorski M, Kim IK, Cho D, Zack D, Souied E, Scholl HP, Bala E, Lee KE, Hunter DJ, Sardell RJ, Mitchell P, Merriam JE, Cipriani V, Hoffman JD, Schick T, Lechanteur YT, Guymer RH, Johnson MP, Jiang Y, Stanton CM, Buitendijk GH, Zhan X, Kwong AM, Boleda A, Brooks M, Gieser L, Ratnapriya R, Branham KE, Foerster JR, Heckenlively JR, Othman MI, Vote BJ, Liang HH, Souzeau E, McAllister IL, Isaacs T, Hall J, Lake S, Mackey DA, Constable IJ, Craig JE, Kitchner TE, Yang Z, Su Z, Luo H, Chen D, Ouyang H, Flagg K, Lin D, Mao G, Ferreyra H, Stark K, von Strachwitz CN, Wolf A, Brandl C, Rudolph G, Olden M, Morrison MA, Morgan DJ, Schu M, Ahn J, Silvestri G, Tsironi EE, Park KH, Farrer LA, Orlin A, Brucker A, Li M, Curcio CA, Mohand-Saïd S, Sahel JA, Audo I, Benchaboune M, Cree AJ, Rennie CA, Goverdhan SV, Grunin M, Hagbi-Levi S, Campochiaro P, Katsanis N, Holz FG, Blond F, Blanché H, Deleuze JF, Igo RP Jr, Truitt B, Peachey NS, Meuer SM, Myers CE, Moore EL, Klein R, Hauser MA, Postel EA, Courtenay MD, Schwartz SG, Kovach JL, Scott WK, Liew G, Tan AG, Gopinath B, Merriam JC, Smith RT, Khan JC, Shahid H, Moore AT, McGrath JA, Laux R, Brantley MA Jr, Agarwal A, Ersoy L, Caramoy A, Langmann T, Saksens NT, de Jong EK, Hoyng CB, Cain MS, Richardson AJ, Martin TM, Blangero J, Weeks DE, Dhillon B, van Duijn CM, Doheny KF, Romm J, Klaver CC, Hayward C, Gorin MB, Klein ML, Baird PN, den Hollander AI, Fauser S, Yates JR, Allikmets R, Wang JJ, Schaumberg DA, Klein BE, Hagstrom SA, Chowers I, Lotery AJ, Léveillard T, Zhang K, Brilliant MH, Hewitt AW, Swaroop A, Chew EY, Pericak-Vance MA, DeAngelis M, Stambolian D, Haines JL, Iyengar SK, Weber BH, Abecasis GR, and Heid IM

Subjects
Genetic Predisposition to Disease, Humans, Mutation, Genome-Wide Association Study, Macular Degeneration genetics
Abstract

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

Published
2016
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10. Advancing therapeutic strategies for inherited retinal degeneration: recommendations from the Monaciano Symposium.

Author

Thompson DA, Ali RR, Banin E, Branham KE, Flannery JG, Gamm DM, Hauswirth WW, Heckenlively JR, Iannaccone A, Jayasundera KT, Khan NW, Molday RS, Pennesi ME, Reh TA, Weleber RG, and Zacks DN

Subjects
Congresses as Topic, Humans, Disease Management, Practice Guidelines as Topic, Retinal Degeneration congenital, Retinal Degeneration therapy
Abstract

Although rare in the general population, retinal dystrophies occupy a central position in current efforts to develop innovative therapies for blinding diseases. This status derives, in part, from the unique biology, accessibility, and function of the retina, as well as from the synergy between molecular discoveries and transformative advances in functional assessment and retinal imaging. The combination of these factors has fueled remarkable progress in the field, while at the same time creating complex challenges for organizing collective efforts aimed at advancing translational research. The present position paper outlines recent progress in gene therapy and cell therapy for this group of disorders, and presents a set of recommendations for addressing the challenges remaining for the coming decade. It is hoped that the formulation of these recommendations will stimulate discussions among researchers, funding agencies, industry, and policy makers that will accelerate the development of safe and effective treatments for retinal dystrophies and related diseases., (Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.)

Published
2015
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11. Differential DNA methylation identified in the blood and retina of AMD patients.

Author

Oliver VF, Jaffe AE, Song J, Wang G, Zhang P, Branham KE, Swaroop A, Eberhart CG, Zack DJ, Qian J, and Merbs SL

Subjects
Aged, Aged, 80 and over, Female, Genotype, Humans, Macular Degeneration blood, Macular Degeneration pathology, Male, Polymorphism, Single Nucleotide, Retina metabolism, Retina pathology, Risk Factors, DNA Methylation genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Macular Degeneration genetics
Abstract

Age-related macular degeneration (AMD) is a major cause of blindness in the western world. While genetic studies have linked both common and rare variants in genes involved in regulation of the complement system to increased risk of development of AMD, environmental factors, such as smoking and nutrition, can also significantly affect the risk of developing the disease and the rate of disease progression. Since epigenetics has been implicated in mediating, in part, the disease risk associated with some environmental factors, we investigated a possible epigenetic contribution to AMD. We performed genome-wide DNA methylation profiling of blood from AMD patients and controls. No differential methylation site reached genome-wide significance; however, when epigenetic changes in and around known GWAS-defined AMD risk loci were explored, we found small but significant DNA methylation differences in the blood of neovascular AMD patients near age-related maculopathy susceptibility 2 (ARMS2), a top-ranked GWAS locus preferentially associated with neovascular AMD. The methylation level of one of the CpG sites significantly correlated with the genotype of the risk SNP rs10490924, suggesting a possible epigenetic mechanism of risk. Integrating genome-wide DNA methylation analysis of retina samples with and without AMD together with blood samples, we further identified a consistent, replicable change in DNA methylation in the promoter region of protease serine 50 (PRSS50). These methylation changes may identify sites in novel genes that are susceptible to non-genetic factors known to contribute to AMD development and progression.

Published
2015
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