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A Newly Identified COCH Mutation Affects the Vwfa2 Domain and Leads to A

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A Newly Identified COCH Mutation Affects the Vwfa2 Domain and Leads to A A newly identified COCH mutation affects the vWFA2 domain and leads to a relatively mild DFNA9 phenotype Supplemental Digital Content Supplemental Methods Annotated variants were filtered, based on a population allele frequency of ≤ 0.05% in the gnomAD exome and genome database V.2.1 (https://gnomad.broadinstitute.org/) and our in-house exome database (containing ~15.000 alleles). Variants in coding and splice site regions (-14/+14 nt) were analyzed. Interpretation of missense variants was performed using the in silico pathogenicity prediction tools CADD-PHRED (≥15) (1), SIFT (≤0.05) (2), PolyPhen-2 (PPH2, ≥0.450) (3) and MutationTaster (deleterious) (4). Only those called variants were considered that had a quality-by- depth >150 and that were associated with an autosomal dominant inherited type of HI. Shared variants in the MIPs data of the selected subjects were analyzed. To address the possible existence of one or more phenocopies, shared variants between two subjects (IV.1 with III.9, IV.1 with III.13 and III.9 with III.13) were also analyzed separately. Variants were considered if a pathogenic effect was predicted by at least two different tools. Potential effects on splicing of missense and synonymous variants were evaluated using five algorithms (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer and Human Splicing Finder) via the AlamutVisual software (V.2.10, Interactive Biosoftware). A change of ≥5% in splice site scores predicted by at least two algorithms was considered significant. Table S1. Hearing loss genes covered by MIPS panel ACTG1 GRM7 PTPRQ ADCY1 GRM8 RDX BDP1 GRXCR1 RIPOR2 BSND GRXCR2 SERPINB6 CABP2 HGF SIX1 CCDC50 ILDR1 SLC17A8 CDH23 KARS SLC26A4 CEACAM16 KCNQ4 SLC26A5 CIB2 LHFPL5 SMPX CLDN14 LOXHD1 STRC CLIC5 LRTOMT SYNE4 COCH MARVELD2 TBC1D24 COL11A2 MIR96 TECTA COL4A6 MSRB3 TJP2 CRYM MYH14 TMC1 DCDC2 MYH9 TMEM132E GSDME MYO15A TMIE DFNB31 MYO3A TMPRSS3 DFNB59 MYO6 TNC DIABLO MYO7A TPRN DIAPH1 NAT2 TRIOBP ELMOD3 OSBPL2 TSPEAR EPS8 OTOA USH1C ESPN OTOF USH1G ESRRB OTOG EYA4 OTOGL GIPC3 P2RX2 GJB2 PCDH15 GJB3 PNPT1 GJB6 POU3F4 GPSM2 POU4F3 GRHL2 PRPS1 Table S2. Detailed information on COCH, cochlin and pathogenicity predictions on the identified COCH variant. Genomic RefSeq RefSeq Gene Genomic cDNA Protein GnomAD_ GnomAD_ CADD_ Mutation positions COCH cochlin SIFT PPH2 PhyloP GERP REVEL symbol change change change E AF (%) G AF (%) PHRED Taster COCH transcript protein chr14:31,34 NM_004 NP_004 g.31,355,3 Disease COCH 3,741- c.1312C>T p.Arg438Cys 3.98E-06 - 23.9 0.05 0.974 1.388 4.06 0.697 086.2 077.1 53C>T causing 31,359,822 Scores that meet the thresholds for a possibly deleterious effect are indicated in red. Thresholds are: CADD-PHRED (≥15)(1), SIFT (<0.05) (2), PolyPhen-2 (≥0.450)(3) and MutationTaster (disease causing)(4), PhyloP (≥2.7)(5), GERP(≥2) (6) and REVEL(>0.5)(7). Genomic positions COCH according to GRCh37/hg19; GnomAD_E AF and GnomAD_G AF, allele frequencies in gnomAD total exome database and genome database, respectively; CADD_PHRED, Combined Annotation Dependent Depletion PHRED score; SIFT, Scale-Invariant Feature Transform; PPH2, PolyPhen-2 score; PhyloP, phylogenetic P-values; GERP, Genomic Evolutionary Rate Profiling; REVEL, Rare Exome Variant Ensemble Learner -, frequency not available. 1. Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nature genetics. 2014;46(3):310-5. 2. Vaser R, Adusumalli S, Leng SN, Sikic M, Ng PC. SIFT missense predictions for genomes. Nature Protocols. 2015;11:1. 3. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nature methods. 2010;7(4):248-9. 4. Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nature Methods. 2014;11:361. 5. Pollard KS, Hubisz MJ, Rosenbloom KR, Siepel A. Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res. 2010;20(1):110-21. 6. Cooper GM, Stone EA, Asimenos G, Program NCS, Green ED, Batzoglou S, et al. Distribution and intensity of constraint in mammalian genomic sequence. Genome Res. 2005;15(7):901-13. 7. Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, Baheti S, et al. REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants. Am J Hum Genet. 2016;99(4):877-85. Page 1 of 2 Figure S1 Linkage analysis The blue lines define the customary LOD score range. The green line demonstrates the maximum LOD score measured genome-wide in this experiment. It appears after all computations are completed. Chromosome 1 Chromosome 2 Chromosome 3 Chromosome 4 Chromosome 5 Chromosome 6 Chromosome 7 Chromosome 8 Chromosome 9 Chromosome 10 Chromosome 11 Chromosome 12 Chromosome 13 Chromosome 14 Chromosome 15 Page 2 of 2 Chromosome 16 Chromosome 17 Chromosome 18 Chromosome 19 Chromosome 20 Chromosome 21 Chromosome 22 Chromosome X W08-2035 I.1 I.2 84 25 II.1 II.2 II.3 II.4 II.5 II.6 II.7 II.8 II.9 47 27 15 54 17 67 ? 45 44 77 35 43 49 51 65 64 70 26 ? III.1 III.2 III.3 III.4 III.5 III.6 III.7 III.8 III.9 III.10 III.11 III.12 III.13 III.14 III.15 III.16 III.17 25 34 5 5 26 2 4 2 1 3 4 21 46 21 22 24 22 51 11 1 1 51 5 1 5 3 1 2 33 11 33 51 51 54 66 63 6 6 63 6 4 6 3 8 3 53 66 53 66 66 66 33 35 25 42 26 43 18 33 31 ? Marker Position (cM) IV.1 IV.2 IV.3 IV.4 IV.5 IV.6 IV.7 IV.8 IV.9 IV.10 D14S1021 23 6 2 5 2 2 4 25 1 3 24 26 24 2 2 31.13 COCH D14S54 31.75 51 1 5 1 5 1 1 51 3 1 52 31 31 1 5 D14S257 31.75 66 3 6 6 6 6 4 63 3 8 63 56 56 2 6 Figure S2. Results of VNTR marker genotyping, affected individual III.13 does not carry the disease allele. The shared haplotype is boxed. The c.1312C>T COCH variant is located between the markers D14S1021 and D14S54. cM, centimorgan. .
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