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Recessive Retinopathy Consequent on Mutant G-Protein Β Subunit 3 (GNB3)

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Recessive Retinopathy Consequent on Mutant G-Protein Β Subunit 3 (GNB3) Supplementary Online Content Arno G, Holder GE, Chakarova C, et al; UK Inherited Retinal Disease Consortium. Recessive retinopathy consequent on mutant G-protein β subunit 3 (GNB3). JAMA Ophthalmol. Published online June 9, 2016. doi:10.1001/jamaophthalmol.2016.1543. eAppendix 1. Methods eAppendix 2. Results: Variant Data eTable 1. Exome Sequencing Homozygous and Double Heterozygous Variants eTable 2. Variants Identified by Direct Sanger Sequencing This supplementary material has been provided by the authors to give readers additional information about their work. © 2016 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 eAppendix 1. Methods Gene panel screening Prior genetic screening comprised direct Sanger sequencing of all coding exons of NR2E3 and a Next Generation Sequencing (NGS) panel of 105 retinal dystrophy genes tested at the Manchester Centre for Genomic Medicine, UK (Gene list below). No Pathogenic mutations were identified. ABHD12 CDH3 GPR179 LRIT3 PCYT1A TRPM1 ACBD5 CEP164 GRM6 LZTFL1 PEX1 TSPAN12 ADAMTS18 CIB2 HARS MFRP PEX2 TUB AHI1 CLN3 HMX1 MVK PEX7 VCAN ARL2BP CNNM4 IFT140 NEK2 PHYH VPS13B BB1P1 CSPP1 IMPG1 NMNAT1 PLA2G5 WDR19 C21orf2 CYP4V2 INPP5E NPHP1 PRPF4 ZNF423 C2ORF86 DTHD1 INVS NPHP3 RAB28 C8ORF37 EMC1 IQCB1 NPHP4 RBP4 CABP4 FLVCR1 ITM2B NYX RPGRIP1L CACNA1F GNAT1 KCNJ13 OAT SDCCAG8 CAPN5 GNPTG KIAA1549 OFD1 SLC24A1 CC2D2A GPR125 KIF11 PANK2 TMEM237 Whole exome sequencing methodology 200ng of genomic DNA were processed according to the Agilent SureSelect XT Library Prep protocol (Agilent Technologies, CA, US) with exons being captured using the SureSelect Exome V5 Capture library. After hybridization and indexing, six samples were pooled and 100bp paired end sequencing was performed (Illumina HiSeq 2500 sequencer) at the University of Leeds Next Generation Sequencing Facility, UK. Reads were aligned to the hg19 human reference sequence (build GRCh37) using Novoalign version 2.08. Duplicate reads were marked using Picard tools MarkDuplicates. Calling was performed using GATK, creating gVCF formatted files for each sample. The individual gVCF files for the exomes discussed in this study, in combination with ~ 3,000 clinical exomes (UCL-exomes consortium), were combined into merged VCF files for each chromosome containing on average 100 samples each. The final variant calling was performed using the GATK Genotype gVCFs module jointly for all samples (cases and controls). Variant quality scores were then re-calibrated according to GATK best practices separately for indels and SNPs. Resulting variants were annotated using ANNOVAR based on Ensembl gene and transcript definitions. Candidate variants were filtered based on function (non- synonymous, presumed loss-of-function or splicing) and MAF (< 0.001). © 2016 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 eAppendix 2. Results: Variant Data WES analysis revealed 25,877 exonic ±5bp variants that passed quality filter; 1080 of which had MAF ≤0.001 in NHLBI GO Exome Sequencing Project (ESP, available at http://evs.gs.washington.edu/EVS/EVS) controls. No likely pathogenic variants were noted in any retinal dystrophy genes. Further variant filtering using an in-house control dataset of approximately 3000 exomes revealed 48 genes containing ≥2 rare (≤0.001 MAF) variants, of which 4 genes were predicted to be probable recessive null assuming double heterozygous null variants were in trans (WDR86, GNB3, TCHH, AVL9, see eTable 1). Homozygosity analysis of all variants revealed 2 ≥10mb stretches of unbroken homozygous SNPs (chr12:235,022-11,214,212 [encompassing the GNB3 locus] and chr19:9,213,396-19,230,868) suggestive of parental relatedness. Analysis of NGS read depth data using ExomeDepthe1 and close scrutiny of reads and coverage of the GNB3 locus using the Integrated Genome Viewer (IGV)e2,e3 was not suggestive of any genomic rearrangements resulting in loss of one allele. Uniparental isodisomy could not be ruled out due to unavailability of parental DNA samples. e1. Plagnol V, Curtis J, Epstein M, et al. A robust model for read count data in exome sequencing experiments and implications for copy number variant calling. Bioinformatics. 2012;28(21):2747‐54. doi:10.1093/bioinformatics/bts526. e2. Robinson JT, Thorvaldsdóttir H, Winckler W, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29(1):24‐6. doi:10.1038/nbt.1754. e3. Thorvaldsdóttir H, Robinson JT, Mesirov JP. Integrative Genomics Viewer (IGV): high‐ performance genomics data visualization and exploration. Brief Bioinform. 2013;14(2):178‐92. doi:10.1093/bib/bbs017. © 2016 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 eTable 1. Exome Sequencing Homozygous and Double Heterozygous Variants Homozygous Functio Exonic signat n Function HUGO Description AA Change ure IQ motif containing 1_156 nonsynonymo GTPase activating protein 50097 exonic us SNV IQGAP3 3 ENSG00000183856:ENST00000491900:exon32:c.C4036G:p.L1346V,ENSG00000183856:ENST00000361170:exon33:c.C4165G:p.L1389V 8_G_C 1_200 nonsynonymo DEAD (Asp‐Glu‐Ala‐Asp) ENSG00000118197:ENST00000331314:exon2:c.A536G:p.E179G,ENSG00000118197:ENST00000367348:exon2:c.A536G:p.E179G,ENSG00 63533 exonic us SNV DDX59 box polypeptide 59 000118197:ENST00000447706:exon2:c.A536G:p.E179G 3_T_C 7_168 nonsynonymo 72905 exonic us SNV AGR2 anterior gradient 2 ENSG00000106541:ENST00000419572:exon1:c.A28G:p.S10G _T_C 7_931 25288 splicing CALCR calcitonin receptor _T_C 7_151 10653 exonic stopgain SNV WDR86 WD repeat domain 86 ENSG00000187260:ENST00000334493:exon1:c.C142T:p.Q48X,ENSG00000187260:ENST00000469830:exon1:c.C142T:p.Q48X 4_G_A 9_148 nonsynonymo FRAS1 related ENSG00000164946:ENST00000380880:exon4:c.C583T:p.P195S,ENSG00000164946:ENST00000380875:exon5:c.C583T:p.P195S,ENSG0000 59229 exonic us SNV FREM1 extracellular matrix 1 0164946:ENST00000380881:exon5:c.C583T:p.P195S,ENSG00000164946:ENST00000422223:exon5:c.C583T:p.P195S _G_A 9_131 nonsynonymo cysteine conjugate‐beta ENSG00000171097:ENST00000320665:exon11:c.A1004T:p.Y335F,ENSG00000171097:ENST00000302586:exon12:c.A1154T:p.Y385F,ENSG 59607 exonic us SNV CCBL1 lyase, cytoplasmic 00000171097:ENST00000436267:exon14:c.A1436T:p.Y479F 4_T_A © 2016 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 ENSG00000066468:ENST00000346997:exon1:c.G34A:p.V12M,ENSG00000066468:ENST00000369056:exon1:c.G34A:p.V12M,ENSG00000 066468:ENST00000369061:exon1:c.G34A:p.V12M,ENSG00000066468:ENST00000336553:exon2:c.G34A:p.V12M,ENSG00000066468:ENS T00000351936:exon2:c.G34A:p.V12M,ENSG00000066468:ENST00000356226:exon2:c.G34A:p.V12M,ENSG00000066468:ENST000003575 55:exon2:c.G34A:p.V12M,ENSG00000066468:ENST00000358487:exon2:c.G34A:p.V12M,ENSG00000066468:ENST00000359354:exon2:c. 10_12 G34A:p.V12M,ENSG00000066468:ENST00000360144:exon2:c.G34A:p.V12M,ENSG00000066468:ENST00000369058:exon2:c.G34A:p.V12 33532 nonsynonymo fibroblast growth factor M,ENSG00000066468:ENST00000369059:exon2:c.G34A:p.V12M,ENSG00000066468:ENST00000369060:exon2:c.G34A:p.V12M,ENSG000 98_C_ exonic us SNV FGFR2 receptor 2 00066468:ENST00000457416:exon2:c.G34A:p.V12M T olfactory receptor, family 11_57 nonsynonymo 52, subfamily N, member 76368 exonic us SNV OR52N4 4 (gene/pseudogene) ENSG00000181074:ENST00000317254:exon1:c.G398A:p.R133H _G_A 11_65 nonsynonymo dynein heavy chain ENSG00000179532:ENST00000527990:exon1:c.G17A:p.R6K,ENSG00000179532:ENST00000354685:exon2:c.G17A:p.R6K,ENSG000001795 19462 exonic us SNV DNHD1 domain 1 32:ENST00000254579:exon3:c.G17A:p.R6K _G_A guanine nucleotide binding protein (G ENSG00000111664:ENST00000537035:exon3:c.C124T:p.R42X,ENSG00000111664:ENST00000435982:exon4:c.C124T:p.R42X,ENSG00000 12_69 protein), beta polypeptide 111664:ENST00000541257:exon4:c.C124T:p.R42X,ENSG00000111664:ENST00000541978:exon4:c.C124T:p.R42X,ENSG00000111664:ENS 52161 exonic stopgain SNV GNB3 3 T00000229264:exon5:c.C124T:p.R42X _C_T 12_11 13369 nonsynonymo coiled‐coil domain ENSG00000173093:ENST00000552694:exon8:c.C1094T:p.P365L,ENSG00000173093:ENST00000545036:exon9:c.C1211T:p.P404L,ENSG00 18_C_ exonic us SNV CCDC63 containing 63 000173093:ENST00000308208:exon10:c.C1331T:p.P444L T leucine rich repeat 19_79 nonsynonymo containing 8 family, 64234 exonic us SNV LRRC8E member E ENSG00000171017:ENST00000306708:exon3:c.A827G:p.Y276C _A_G 19_81 nonsynonymo ENSG00000142449:ENST00000270509:exon54:c.C6826T:p.R2276W,ENSG00000142449:ENST00000600128:exon55:c.C6826T:p.R2276W, 51138 exonic us SNV FBN3 fibrillin 3 ENSG00000142449:ENST00000601739:exon55:c.C6826T:p.R2276W _G_A 19_11 nonsynonymo SWIM‐type zinc finger 7 48619 exonic us SNV SWSAP1 associated protein 1 ENSG00000173928:ENST00000312423:exon2:c.G194A:p.R65H 6_G_A © 2016 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 19_13 nonsynonymo synaptonemal complex 01088 exonic us SNV SYCE2 central element protein 2 ENSG00000161860:ENST00000293695:exon5:c.C545T:p.P182L 5_G_A C3 and PZP‐like, alpha‐2‐ 19_17 nonsynonymo macroglobulin domain 08689 exonic us SNV CPAMD8 containing 8 ENSG00000160111:ENST00000443236:exon16:c.C1964T:p.A655V 7_G_A ENSG00000130479:ENST00000324096:exon1:c.G23T:p.G8V,ENSG00000130479:ENST00000594212:exon1:c.G23T:p.G8V,ENSG000001304 19_17 nonsynonymo microtubule‐associated 79:ENST00000597735:exon1:c.G23T:p.G8V,ENSG00000130479:ENST00000600186:exon1:c.G23T:p.G8V,ENSG00000130479:ENST000006 83033 exonic us SNV MAP1S protein 1S 00608:exon1:c.G23T:p.G8V
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