Unravelling the genetic basis of simplex Retinitis Pigmentosa cases

Transcription

1 SUPPLEMENTARY INFORMATION Unravelling the genetic basis simplex Retinitis Pigmentosa cases Nereida Bravo-Gil 1,2#, María González-del Pozo 1,2#, Marta Martín-Sánchez 1, Cristina Méndez-Vidal 1,2, Enrique Rodríguez-de la Rúa 3,4, Salud Borrego 1,2 and Guillermo Antiñolo 1,2* 1 Department Genetics, Reproduction and Fetal Medicine, Institute Biomedicine Seville, University Hospital Virgen del Rocío/CSIC/University Seville, Seville, Spain. 2 Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain. 3 Department Ophthalmology, University Hospitals Virgen Macarena and Virgen del Rocío, Seville, Spain. 4 Retics Patologia Ocular. OFTARED. Instituto Salud Carlos III. # These authors contributed equally to this work. * Corresponding author: Guillermo Antiñolo, MD, PhD Department Genetics, Reproduction and Fetal Medicine University Hospital Virgen del Rocio Av. Manuel Siurot s/n 41013, Seville. Spain guillermo.antinolo.sspa@juntadeandalucia.es

2 Manuscript # SREP : Unravelling the genetic basis simplex Retinitis Pigmentosa cases Nereida Bravo-Gil, María González-del Pozo, Marta Martín-Sánchez, Cristina Méndez-Vidal, Enrique Rodríguez-de la Rúa, Salud Borrego and Guillermo Antiñolo. Supplementary Table S1: in solved cases initially diagnosed s. ad: Autosomal dominant; CRD: Cone rod Dystrophy; F: Female; LCA: Leber Congenital Amaurosis; M: Male; : Not available; : Retinitis Pigmentosa; E: Retinal pigment epithelium; STGD: Stargardt disease; xl: X-Linked. ID Age 2 F 30 4 F 8 visual F M F Birth < 1 14 F F M F M M F 5 months Unknown 29 M 2 11 Reduced visual, Central scotoma, night blindness, discromatopsy Reduced visual, Reduced visual, Reduced visual, Reduced visual,, Reduced visual, Night blindness and Intense (better scotopic vision) 0.2/0.3 Light perception <0.1/<0.1 Bone spicule pigmentation, pallor the Pigment deposits in macula STGD Bone spicule pigmentation. Narrowed vessels. Macular atrophy. Abolished Farnsworth Test: not recordable (OD) and discromatopsy (OS) Choroideremia Nystagmus LCA 0.1/0.05 Abolished 0.3/0.4 Bone spicule pigmentation, Abolished Cataract, suspected Meniere's disease 0.1/0.1 Macular atrophy LCA LCA 0.7/0.7 Abolished 33 M Unknown LCA E changes in the periphery, 35 M /0.7 peripapillary atrophy, salt and peeper responses fundus. 36 F Unknown 37 F 4 39 M M F 7 Reduced visual, the visual, night blindness, decreased Reduced visual (10º central), 0.1/ / /0.5 Pigment deposits in macula, bonespicule pigmentation in the equatorial retina Salt and pepper retinopathy, E changes in the periphery, normal optic disc and blood vessels Bone spicule pigmentation, pallor the Nystagmus, strabismus LCA 45 M 0.32/ F 13 reduced visual vessels Cataracts Abolished Photophobia 48 M Birth Unknown Nystagmus, obesity 49 F Birth 11 reduced visual 0.6/0.2 Bone spicule pigmentation (mild) 50 F /0.3 Bone spicule pigmentation 51 M 2 5 reduced Bone spicule pigmentation and pale 1/0.8 visual optic discs 53 F 24 Typical advanced with <0.05/<0.05 affectation 55 M Birth Total blindness No light Retinal dystrophy, bone spicule perception pigmentation 56 F E changes in the periphery, Reduced visual, perifoveal atrophy, bone-spicule 0.6/0.5 pigmentation in the equatorial retina, pallor the optic discs 59 M Birth M /0.2 Cataracts Photophobia CRD Abolished. Delayed visual evoked potentials 0.7/0.6 Optic disc pallor Abolished Myopia Cataracts,, hearing loss (supposedly after an ear infection) 61 F Unknown LCA Strabismus, hypermetropia, 65 F Tapetoretinal degeneration xlcrd astigmatism, USHER 2

3 ID Age visual 66 F 22 the visual (20º central), 0.8/ F Night blindness 1/1 69 M 70 F F M 74 M 76 F 78 F Unknown M F 83 M F M M F M / reduction the visual 36 8 the visual (5º central), Reduced visual and, night blindness Reduced visual, the visual, night blindness, decreased Reduced visual, the visual (8º central); Preserved Reduced visual, night blindness reduced visual,, 94 M constriction, decreased visual acuity 95 F 1 97 F reduced visual,, 0.4/0.4 Bone spicule pigmentation, pallor the Bone spicule deposits predominant in the superior part the retina resembling sector (inferior temporal sector free), narrowed vessels, normal macula. 0.1/0.1 sine pigmento', narrowed vessels 0.7/0.8 Increase the brightness internal limiting membrane. Bone spicule pigmentation outside the vascular arcade (sector) Post-traumatic hearing loss Abolished Myopia 0.5/ /0.3 Tigroid fundus Abolished astigmatism 0.3/0.2 and atrophy Narrowed vessels, fundus albipunctatus, normal optic discs, drusen near the fovea Abolished Farnsworth Test: discromatopsy/ hearing loss at 49 years old astigmatism, slow progression, cataract Maculopathy LCA E atrophy Abolished Myopia magna Choroideremia 0.2/0.1 Bilateral atrophy Pallor the optic discs, narrowed vessels, bone spicules in the periphery, peripappilary atrophy with relatively preserved macula Strabismus since 9 months age, nystagmus Nystagmus 100 F 25 Unknown Abolished 101 M 7 reduced visual, decreased Cephalea 102 F F F M M M F F reduced visual LCA with early Photophobia, myopia, astigmatism Astigmatism Photophobia Cataracts 0.6/0.5 CRD Hearing loss USHER CRD 3

4 ID Age 119 M 20 visual 25 Reduced visual, 122 M Unknown STGD Atypical fundus. Pigment deposits 116 F 14 reduced within temporal superior vascular / visual, decreased arcade, yellowish waxy optic disc, Strabismus,, color vision inferior drusen, posterior pole cataracts alteration chorioretinal atrophy, discrete Choroideremia pigmentary deposits 4

5 Manuscript # SREP : Unravelling the genetic basis simplex Retinitis Pigmentosa cases Nereida Bravo-Gil, María González-del Pozo, Marta Martín-Sánchez, Cristina Méndez-Vidal, Enrique Rodríguez-de la Rúa, Salud Borrego and Guillermo Antiñolo. Supplementary Table S2: Unsolved cases carrying one likely pathogenic allele. Allele frequency data derived from ExAC (The Exome Aggregation Consortium). ESCS: Enhanced S-cone Syndrome; FFM: Fundus flavimaculatus; LCA: Leber Congenital Amaurosis; : Retinitis pigmentosa; STGD: Stargardt disease; VUS: Variant significance. ID Phenotype Gene Exon cd Protein Status Reference Allele frequency Interpretation 113 ABCA4 42 c.5882g>a p.g1961e Het Cella et al., Exp Eye Res (2009). rs Pathogenic STGD with early with early ABCA4 43 c.5908c>t p.l1970f Het ABCA4 45 c.6148g>c p.v2050l Het 98 ABCA4 45 c.6148g>c p.v2050l Het 64 ABCA4 46 c.6148g>c p.v2050l Het 43 GPR98 39 c.8779g>a p.v2927i Het 96 Non syndromic Rozet el al., Eur J Hum Genet. (1998). rs rs E-05 Pathogenic Late FFM BBS12 2 c.1114_1115del p.f372fs Het This study 5.78E-05 Likely pathogenic 110 LCA CEP c.2691a>g p.i897m Het This study 2.11E-05 Likely pathogenic 28 CEP c.3517c>a p.q1173k Het This study 3.78E-05 Likely pathogenic 26 CNGB3 14 c.1627g>a p.v543i Het This study 1.66E-05 Likely pathogenic 57 EYS Deletion exons Unable to predict Het Abd-El Aziz et al. (2008) - Pathogenic 19 EYS Deletion exons Unable to predict Het Audo et al., Hum Mutat - Pathogenic (2010) 25 GPR98 59 c.12208g>a p.v4070i Het rs E-05 VUS 109 with early NR2E3 6 c.932g>a p.r311q Het Haider et al.,. (2000). rs rs VUS Pathogenic ESCS Goldmann-favre syndrome 99 LCA PCDH15 35 c.5296_5304dupgctcctcct p.a1766_p1768du p Het VUS c.6196_6198del p.d2066del Het This study - Likely pathogenic 105 GRIP1 10 c.1220dupa p.q408fs Het This study - Likely pathogenic 82 USH2A 27 c.5363a>g p.d1788g Het This study 8.24E-06 Likely pathogenic 5