Molecular diagnosis of putative Stargardt disease probands by exome sequencing

BMC Medical Genetics

Michael B Gorin²  Deborah B Farber²  Steven Nusinowitz²  Stanley F Nelson¹  Zugen Chen¹  Carolina Ortube²  Ariadna Martinez²  Yong-Qing Gao²  Samuel P Strom² 

[1] Department of Human Genetics, University of California Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA, 90095, USA;Jules Stein Eye Institute, University of California Los Angeles, 200 Stein Plaza, Los Angeles, CA, 90095, USA

关键词: PRPH2;    ABCA4;    Molecular Diagnostics;    Mutation Screening;    Exome;    Macular Degeneration;    Stargardt Disease;   

Others  :  1177819
DOI  :  10.1186/1471-2350-13-67

 received in 2012-04-11, accepted in 2012-07-25,  发布年份 2012

【 摘 要 】

Background

The commonest genetic form of juvenile or early adult onset macular degeneration is Stargardt Disease (STGD) caused by recessive mutations in the gene ABCA4. However, high phenotypic and allelic heterogeneity and a small but non-trivial amount of locus heterogeneity currently impede conclusive molecular diagnosis in a significant proportion of cases.

Methods

We performed whole exome sequencing (WES) of nine putative Stargardt Disease probands and searched for potentially disease-causing genetic variants in previously identified retinal or macular dystrophy genes. Follow-up dideoxy sequencing was performed for confirmation and to screen for mutations in an additional set of affected individuals lacking a definitive molecular diagnosis.

Results

Whole exome sequencing revealed seven likely disease-causing variants across four genes, providing a confident genetic diagnosis in six previously uncharacterized participants. We identified four previously missed mutations in ABCA4 across three individuals. Likely disease-causing mutations in RDS/PRPH2, ELOVL, and CRB1 were also identified.

Conclusions

Our findings highlight the enormous potential of whole exome sequencing in Stargardt Disease molecular diagnosis and research. WES adequately assayed all coding sequences and canonical splice sites of ABCA4 in this study. Additionally, WES enables the identification of disease-related alleles in other genes. This work highlights the importance of collecting parental genetic material for WES testing as the current knowledge of human genome variation limits the determination of causality between identified variants and disease. While larger sample sizes are required to establish the precision and accuracy of this type of testing, this study supports WES for inherited early onset macular degeneration disorders as an alternative to standard mutation screening techniques.

【 授权许可】

   
2012 Strom et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Nasonkin I, Illing M, Koehler MR, Schmid M, Molday RS, Weber BH: Mapping of the rod photoreceptor ABC transporter (ABCR) to 1p21-p22.1 and identification of novel mutations in Stargardt's disease. Hum Genet 1998, 102(1):21-26.
• [2]Rozet JM, Gerber S, Souied E, Perrault I, Châtelin S, Ghazi I, Leowski C, Dufier JL, Munnich A, Kaplan J: Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies. Eur J Hum Genet 1998, 6(3):291-295.
• [3]Allikmets R, Singh N, Sun H, Shroyer NF, Hutchinson A, Chidambaram A, Gerrard B, Baird L, Stauffer D, Peiffer A, et al.: A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet 1997, 15(3):236-246.
• [4]Coco RM, Tellería JJ, Sanabria MR, Rodríguez-Rúa E, García MT: PRPH2 (Peripherin/RDS) mutations associated with different macular dystrophies in a Spanish population: a new mutation. Eur J Ophthalmol 2010, 20(4):724-732.
• [5]Poloschek CM, Bach M, Lagrèze WA, Glaus E, Lemke JR, Berger W, Neidhardt J: ABCA4 and ROM1: implications for modification of the PRPH2-associated macular dystrophy phenotype. Invest Ophthalmol Vis Sci 2010, 51(8):4253-4265.
• [6]Petrukhin K, Koisti MJ, Bakall B, Li W, Xie G, Marknell T, Sandgren O, Forsman K, Holmgren G, Andreasson S, et al.: Identification of the gene responsible for Best macular dystrophy. Nat Genet 1998, 19(3):241-247.
• [7]Edwards AO, Donoso LA, Ritter R: A novel gene for autosomal dominant Stargardt-like macular dystrophy with homology to the SUR4 protein family. Invest Ophthalmol Vis Sci 2001, 42(11):2652-2663.
• [8]Zhang K, Kniazeva M, Han M, Li W, Yu Z, Yang Z, Li Y, Metzker ML, Allikmets R, Zack DJ, et al.: A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nat Genet 2001, 27(1):89-93.
• [9]Vasireddy V, Wong P, Ayyagari R: Genetics and molecular pathology of Stargardt-like macular degeneration. Prog Retin Eye Res 2010, 29(3):191-207.
• [10]Yang Z, Chen Y, Lillo C, Chien J, Yu Z, Michaelides M, Klein M, Howes KA, Li Y, Kaminoh Y, et al.: Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice. J Clin Invest 2008, 118(8):2908-2916.
• [11]Simonelli F, Testa F, Zernant J, Nesti A, Rossi S, Allikmets R, Rinaldi E: Genotype-phenotype correlation in Italian families with Stargardt disease. Ophthalmic Res 2005, 37(3):159-167.
• [12]Passerini I, Sodi A, Giambene B, Mariottini A, Menchini U, Torricelli F: Novel mutations in of the ABCR gene in Italian patients with Stargardt disease. Eye (Lond) 2010, 24(1):158-164.
• [13]Paloma E, Martínez-Mir A, Vilageliu L, Gonzàlez-Duarte R, Balcells S: Spectrum of ABCA4 (ABCR) gene mutations in Spanish patients with autosomal recessive macular dystrophies. Hum Mutat 2001, 17(6):504-510.
• [14]Aguirre-Lamban J, Riveiro-Alvarez R, Maia-Lopes S, Cantalapiedra D, Vallespin E, Avila-Fernandez A, Villaverde-Montero C, Trujillo-Tiebas MJ, Ramos C, Ayuso C: Molecular analysis of the ABCA4 gene for reliable detection of allelic variations in Spanish patients: identification of 21 novel variants. Br J Ophthalmol 2009, 93(5):614-621.
• [15]Fukui T, Yamamoto S, Nakano K, Tsujikawa M, Morimura H, Nishida K, Ohguro N, Fujikado T, Irifune M, Kuniyoshi K, et al.: ABCA4 gene mutations in Japanese patients with Stargardt disease and retinitis pigmentosa. Invest Ophthalmol Vis Sci 2002, 43(9):2819-2824.
• [16]Maia-Lopes S, Aguirre-Lamban J, Castelo-Branco M, Riveiro-Alvarez R, Ayuso C, Silva ED: ABCA4 mutations in Portuguese Stargardt patients: identification of new mutations and their phenotypic analysis. Mol Vis 2009, 15:584-591.
• [17]Hargitai J, Zernant J, Somfai GM, Vamos R, Farkas A, Salacz G, Allikmets R: Correlation of clinical and genetic findings in Hungarian patients with Stargardt disease. Invest Ophthalmol Vis Sci 2005, 46(12):4402-4408.
• [18]Duno M, Schwartz M, Larsen PL, Rosenberg T: Phenotypic and genetic spectrum of Danish patients with ABCA4-related retinopathy. Ophthalmic Genet 2012. [Epub ahead of print]
• [19]Jaakson K, Zernant J, Külm M, Hutchinson A, Tonisson N, Glavac D, Ravnik-Glavac M, Hawlina M, Meltzer MR, Caruso RC, et al.: Genotyping microarray (gene chip) for the ABCR (ABCA4) gene. Hum Mutat 2003, 22(5):395-403.
• [20]Zernant J, Schubert C, Im KM, Burke T, Brown CM, Fishman GA, Tsang SH, Gouras P, Dean M, Allikmets R: Analysis of the ABCA4 gene by next-generation sequencing. Invest Ophthalmol Vis Sci 2011, 52(11):8479-8487.
• [21]Audo I, Bujakowska KM, Leveillard T, Mohand-Said S, Lancelot ME, Germain A, Antonio A, Michiels C, Saraiva JP, Letexier M, et al.: Development and application of a next-generation-sequencing (NGS) approach to detect known and novel gene defects underlying retinal diseases. Orphanet J Rare Dis 2012, 7(1):8. BioMed Central Full Text
• [22]Chen B, Tosha C, Gorin MB, Nusinowitz S: Analysis of autofluorescent retinal images and measurement of atrophic lesion growth in Stargardt disease. Exp Eye Res 2010, 91(2):143-152.
• [23]Clark MJ, Chen R, Lam HY, Karczewski KJ, Euskirchen G, Butte AJ, Snyder M: Performance comparison of exome DNA sequencing technologies. Nat Biotechnol 2011, 29(10):908-914.
• [24]Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R: The Sequence Alignment/Map format and SAMtools. Bioinformatics 2009, 25(16):2078-2079.
• [25]McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, et al.: The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 2010, 20(9):1297-1303.
• [26]National Heart Lung and Blood Association, National Human Genome Research Institute: SeattleSeq Annotation 131. University of Washington, Seattle, WA; 2011.
• [27]González-Pérez A, López-Bigas N: Improving the assessment of the outcome of nonsynonymous SNVs with a consensus deleteriousness score, Condel. Am J Hum Genet 2011, 88(4):440-449.
• [28]Testa F, Marini V, Rossi S, Interlandi E, Nesti A, Rinaldi M, Varano M, Garré C, Simonelli F: A novel mutation in the RDS gene in an Italian family with pattern dystrophy. Br J Ophthalmol 2005, 89(8):1066-1068.
• [29]Aleman TS, Cideciyan AV, Aguirre GK, Huang WC, Mullins CL, Roman AJ, Sumaroka A, Olivares MB, Tsai FF, Schwartz SB, et al.: Human CRB1-associated retinal degeneration: comparison with the rd8 Crb1-mutant mouse model. Invest Ophthalmol Vis Sci 2011, 52(9):6898-6910.
• [30]Meunier I, Sénéchal A, Dhaenens CM, Arndt C, Puech B, Defoort-Dhellemmes S, Manes G, Chazalette D, Mazoir E, Bocquet B, et al.: Systematic Screening of BEST1 and PRPH2 in Juvenile and Adult Vitelliform Macular Dystrophies: A Rationale for Molecular Analysis. Ophthalmology 2011, 118(6):1130-1136. Epub 2011 Jan 26
• [31]Bonnefond A, Durand E, Sand O, De Graeve F, Gallina S, Busiah K, Lobbens S, Simon A, Bellanné-Chantelot C, Létourneau L, et al.: Molecular diagnosis of neonatal diabetes mellitus using next-generation sequencing of the whole exome. PLoS One 2010, 5(10):e13630.
• [32]Sohocki MM, Daiger SP, Bowne SJ, Rodriquez JA, Northrup H, Heckenlively JR, Birch DG, Mintz-Hittner H, Ruiz RS, Lewis RA, et al.: Prevalence of mutations causing retinitis pigmentosa and other inherited retinopathies. Hum Mutat 2001, 17(1):42-51.
• [33]Lim KP, Yip SP, Cheung SC, Leung KW, Lam ST, To CH: Novel PRPF31 and PRPH2 mutations and co-occurrence of PRPF31 and RHO mutations in Chinese patients with retinitis pigmentosa. Arch Ophthalmol 2009, 127(6):784-790.
• [34]Feist RM, White MF, Skalka H, Stone EM: Choroidal neovascularization in a patient with adult foveomacular dystrophy and a mutation in the retinal degeneration slow gene (Pro 210 Arg). Am J Ophthalmol 1994, 118(2):259-260.
• [35]Jacobson SG, Cideciyan AV, Kemp CM, Sheffield VC, Stone EM: Photoreceptor function in heterozygotes with insertion or deletion mutations in the RDS gene. Invest Ophthalmol Vis Sci 1996, 37(8):1662-1674.
• [36]Trujillo MJ, Bueno J, Osorio A, Sanz R, Garcia-Sandoval B, Ramos C, Ayuso C: Three novel RDS-peripherin mutations (689delT, 857del17, G208D) in Spanish families affected with autosomal dominant retinal degenerations. Mutations in brief no. 147. Online. Hum Mutat 1998, 12(1):70.
• [37]Renner AB, Fiebig BS, Weber BH, Wissinger B, Andreasson S, Gal A, Cropp E, Kohl S, Kellner U: Phenotypic variability and long-term follow-up of patients with known and novel PRPH2/RDS gene mutations. Am J Ophthalmol 2009, 147(3):518-530. e511
• [38]Boon CJ, van Schooneveld MJ, den Hollander AI, van Lith-Verhoeven JJ, Zonneveld-Vrieling MN, Theelen T, Cremers FP, Hoyng CB, Klevering BJ: Mutations in the peripherin/RDS gene are an important cause of multifocal pattern dystrophy simulating STGD1/fundus flavimaculatus. Br J Ophthalmol 2007, 91(11):1504-1511.
• [39]Lois N, Holder GE, Bunce C, Fitzke FW, Bird AC: Phenotypic subtypes of Stargardt macular dystrophy-fundus flavimaculatus. Arch Ophthalmol 2001, 119(3):359-369.
• [40]Downes SM, Fitzke FW, Holder GE, Payne AM, Bessant DA, Bhattacharya SS, Bird AC: Clinical features of codon 172 RDS macular dystrophy: similar phenotype in 12 families. Arch Ophthalmol 1999, 117(10):1373-1383.
• [41]den Hollander AI, Davis J, van der Velde-Visser SD, Zonneveld MN, Pierrottet CO, Koenekoop RK, Kellner U, van den Born LI, Heckenlively JR, Hoyng CB, et al.: CRB1 mutation spectrum in inherited retinal dystrophies. Hum Mutat 2004, 24(5):355-369.
• [42]Travis GH, Sutcliffe JG, Bok D: The retinal degeneration slow (rds) gene product is a photoreceptor disc membrane-associated glycoprotein. Neuron 1991, 6(1):61-70.
• [43]Li Y, Vinckenbosch N, Tian G, Huerta-Sanchez E, Jiang T, Jiang H, Albrechtsen A, Andersen G, Cao H, Korneliussen T, et al.: Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants. Nat Genet 2010, 42(11):969-972.