Comprehensive genetic testing for hearing and vision loss

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1 Comprehensive genetic testing for hearing and vision loss

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3 Hearing and vision loss can result from both genetic and non-genetic etiologies In general, there is a genetic basis for up to 50% of prelingual hearing loss and up to 60% of congenital blindness among infants. Indications for genetic testing for deafness and/or vision loss may include Clinical status: To confirm a clinical diagnosis in an affected patient, in an individual with unknown status (who has not received screening or evaluation), or in unaffected relatives of an affected patient (who have had normal screenings and/or evaluations). The purpose of the test may be diagnostic, carrier testing, familial follow-up on a known family variant, or prenatal testing for known variant(s) Treatment: To clarify the cause of hearing and/or vision loss, provide information on the likelihood of related health issues, and guide treatment Family risk: To establish risk to other family members and future generations. Genetic testing can help family members who are susceptible to certain drugs avoid drug-induced hearing loss. For example, aminoglycoside drugs can cause hearing loss in individuals with mutations in the MT-RNR1 gene. Furthermore, testing can confirm syndromic conditions, enabling early detection and surveillance for defects in other organs The disorders included in our hearing and vision loss panels may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner For genes displaying an autosomal dominant mode of inheritance, an affected parent carrying the mutated gene has a 1 in 2 chance of passing the variant on to a child, regardless of gender. Some of these genes are not fully penetrant, meaning that an individual may have a mutated gene. but not display any signs or symptoms of the disorder. Additionally, these disorders may have variable expressivity. For diseases with autosomal recessive inheritance, there is a 1 in 4 chance of having a child who is affected by the disease if both parents are carriers. The parents of an affected child are most often obligate carriers (heterozygotes) and each carry one mutant allele, unless a de novo mutation occurs. An X-linked inheritance means that there is a 1 in 2 chance that a male child will be affected by the disorder if the mother carries an X-linked mutation. Depending on the X-inactivation pattern of the gene, a mother and her daughters rarely may be affected. Although X-linked diseases are normally transmitted from mother to son, transmission of an X-linked mutation will occur from an affected father to each daughter, but will not occur from father to son.

4 Genetic testing options for hearing and vision loss The Comprehensive Hearing and Vision Loss Panel detects pathogenic variants in 308 genes. It encompasses two smaller panels the Comprehensive Vision Loss Panel and the Comprehensive Hearing Loss Panel. Comprehensive Hearing and Vision Loss Panel (308 genes) Comprehensive Vision Loss Panel (250 genes) Comprehensive Hearing Loss Panel (92 genes) ABCA4 ABHD12 ADAM9 AGK AHI1 AIPL1 ALMS1 AP3B1 ARL13B ARL6 BBS1 BBS10 BBS12 BBS2 BBS4 BBS5 BBS7 BBS9 BCOR BEST1 BLOC1S6 BMP4 C2orf71 C5orf42 C8orf37 CA4 CABP4 CACNA1F CACNA2D4 CAPN5 CC2D2A CDH3 CDHR1 CEP164 CEP290 CEP41 CERKL CHM CLN3 CLN5 CLN6 CLN8 CNGA1 CNGA3 CNGB1 CNGB3 CNNM4 COL11A1 COL2A1 COL9A1 COL9A2 CRB1 CRX CRYAA CRYAB CRYBB1 CRYBB3 CTSD CYP1B1 CYP4V2 DHDDS DNAJC5 EFEMP1 ELOVL4 ERCC6 EYS FAM161A FLVCR1 FOXC1 FOXE3 FRAS1 FREM1 FREM2 FRMD7 FSCN2 FYCO1 FZD4 GCNT2 GJA8 GNAT1 GNAT2 GNPTG GPR143 GPR179 GRIP1 GRK1 GRM6 GUCA1A GUCA1B GUCY2D HCCS HESX1 HPS1 HPS3 HPS4 HPS5 HPS6 HSF4 IFT140 IMPDH1 IMPG2 INPP5E IQCB1 JAG1 KCNJ13 KCNV2 KIF11 KIF7 KLHL7 LCA5 LRAT LRIT3 LRP5 LYST LZTFL1 MAK MERTK MFRP MFSD8 MKKS MKS1 MTTP MYOC NDP NMNAT1 NPHP1 NPHP3 NPHP4 NR2E3 NRL NYX OAT OCA2 OFD1 OPA3 OPN1SW OTX2 PANK2 PAX6 PDE6A PDE6B PDE6C PDE6G PDE6H PGK1 PITPNM3 PITX2 PITX3 PLA2G5 PPT1 PRCD PROM1 PRPF3 PRPF31 PRPF6 PRPF8 PRPH2 PXDN RAB28 RAX2 RBP3 RBP4 RD3 RDH12 RDH5 RGR RGS9 RGS9BP RHO RIMS1 RLBP1 ROM1 RP1 RP1L1 RP2 RPE65 RPGR RPGRIP1 RPGRIP1L RS1 SAG SDCCAG8 SEMA4A SLC24A1 SLC45A2 SMOC1 SNRNP200 SOX2 SPATA7 STRA6 TCTN1 TCTN2 TCTN3 TDRD7 TGFBI TIMP3 TMEM216 TMEM231 TMEM237 TMEM67 TOPORS TPP1 TREX1 TRIM32 TRPM1 TSPAN12 TTC21B TTC8 TULP1 TYR TYRP1 UBIAD1 VCAN VSX2 WDR19 ZNF423 ADGRV1 CDH23 CIB2 CLRN1 COL11A2 EDN3 EDNRB EYA1 HARS MITF MYH9 MYO7A OPA1 PAX3 PCDH15 PEX1 PEX10 PEX14 PEX16 PEX19 PEX2 PEX5 PEX6 PEX7 PHYH PRPS1 SOX10 TIMM8A TMEM126A USH1C USH1G USH2A WFS1 WHRN ACTG1 AIFM1 CACNA1D CCDC50 CEACAM16 CLDN14 COCH DFNA5 DFNB59 DIABLO DIAPH1 ESPN ESRRB EYA4 GIPC3 GJB2 GJB6 GPSM2 GRHL2 GRXCR1 HGF ILDR1 KARS KCNQ1 KCNQ4 LHFPL5 LOXHD1 LRTOMT MARVELD2 MSRB3 MT-RNR1 MYH14 MYO15A MYO3A MYO6 OTOA OTOF OTOG OTOGL P2RX2 POU3F4 POU4F3 PTPRQ RDX SERPINB6 SIX1 SIX5 SLC26A4 SMPX STRC TBC1D24 TECTA TMC1 TMIE TMPRSS3 TPRN TRIOBP TSPEAR All genes were selected for inclusion based on literature review, clinical actionability scores, and comparison with commercially available assays.

5 Comprehensive Vision Loss Panel (250 genes) CRB1 CYP4V2 DHDD2 EYS FAM161A FLVCR1 FSCN2 GNAT2 GPR179 GRK1 GRM6 GUCA1A GUCA1B GUCY2D HARS IFT140 IMPDH1 IMPG2 INPP5E IQCB1 KCNV2 KIF7 KLHL7 LCA5 LRAT LRIT3 LZTFL1 MAK MERTK MKKS MKS1 MYO7A NMNAT1 NPHP1 NPHP3 NPHP4 Retinal Disease Subpanel (154 genes) Developmental Eye Subpanel (21 genes) Albinism, Hermansky-Pudlak Syndrome, and Waardenburg Syndrome Subpanel (18 genes) Stickler and Cataract Subpanel (41 genes) CABP4 CDH3 CLN3 CLN5 CLN6 CLN8 CTSD CYP1B1 DNAJC5 EFEMP1 ELOVL4 FRMD7 FZD4 GNAT1 HESX1 LYST MFSD8 MTTP MYOC NYX PGK1 PITX2 PPT1 RGS9 RGS9BP RS1 TGFBI TIMM8A TIMP3 TPP1 TREX1 TSPAN12 UBIAD1 ABCA4 ADAM9 ADGRV1 AHI1 AIPL1 ALMS1 ARL13B ARL6 BBS1 BBS10 BBS12 BBS2 BBS4 BBS5 BBS7 BBS9 C2orf71 C5orf42 C8orf37 CA4 CACNA2D4 CC2D2A CDH23 CDHR1 CEP164 CEP290 CEP41 CERKL CHM CIB2 CLRN1 CNGA1 CNGA3 CNGB1 CNGB3 CNNM4 NR2E3 NRL OFD1 OPA1 OPN1SW PANK2 PCDH15 PDE6A PDE6B PDE6C PDE6G PDE6H PEX1 PEX10 PEX14 PEX19 PEX2 PEX5 PEX6 PITPNM3 PRCD PROM1 PRPF3 PRPF31 PRPF6 PRPF8 PRPH2 PRPS1 RAB28 RAX2 RBP3 RBP4 RD3 RDH12 RDH5 RGR RHO RIMS1 ROM1 RP1 RP1L1 RP2 RPE65 RPGR RPGRIP1 RPGRIP1L SAG SDCCAG8 SEMA4A SLC24A1 SNRNP200 SPATA7 TCTN1 TCTN2 TCTN3 TMEM126A TMEM216 TMEM231 TMEM237 TMEM67 TOPORS TRIM32 TRPM1 TTC21B TTC8 TULP1 USH1C USH1G USH2A WDR19 WHRN ZNF423 CACNA1F AP3B1 BLOC1S6 EDN3 EDNRB GPR143 HPS1 HPS3 HPS4 HPS5 HPS6 MITF OCA2 PAX3 SLC45A2 SOX10 TYR TYRP1 BMP4 FOXC1 FOXE3 FRAS1 FREM1 FREM2 GRIP1 HCCS K1F11 PLA2G5 SMOC1 SOX2 STRA6 PAX6 PITX3 PXDN VSX2 BCOR NDP OTX2 AGK COL11A1 COL11A2 COL2A1 COL9A1 COL9A2 CRYAA CRYAB CRYBB1 CRYBB3 ERCC6 EYA1 FYCO1 GCNT2 GJA8 GNPTG HSF4 JAG1 LRP5 MYH9 OAT OPA3 PEX7 TDRD7 VCAN WFS1 MFRP ABHD12 BEST1 CAPN5 CRX KCNJ13 PEX16 PHYH RLBP1

6 Genetic testing options for hearing and vision loss (cont d) Comprehensive Hearing Loss Panel (92 genes) Zellweger Syndrome Subpanel (9 genes) Branchio-Oto-Renal Syndrome Subpanel (3 genes) Usher Syndrome Subpanel (11 genes) ACTG1 AIFM1 CACNA1D CCDC50 CEACAM16 CLDN14 COCH COL11A2 DFNA5 DFNB59 DIABLO DIAPH1 EDN3 EDNRB ESPN ESRRB EYA4 GIPC3 GJB2 GJB6 GPSM2 GRHL2 GRXCR1 HGF ILDR1 KARS KCNQ1 KCNQ4 LHFPL5 LOXHD1 LRTOMT MARVELD2 MITF MSRB3 MT-RNR1 MYH14 MYH9 MYO15A MYO3A MYO6 OPA1 OTOA OTOF OTOG OTOGL P2RX2 PAX3 PHYH POU3F4 POU4F3 PRPS1 PTPRQ RDX SERPINB6 SLC26A4 SMPX SOX10 STRC TBC1D24 TECTA TIMM8A TMC1 TMEM126A TMIE TMPRSS3 TPRN TRIOBP TSPEAR WFS1 PEX1 PEX10 PEX14 PEX16 PEX19 PEX2 PEX5 PEX6 PEX7 EYA1 SIX1 SIX5 ADGRV1 CDH23 CIB2 CLRN1 HARS MYO7A PCDH15 USH1C USH1G USH2A WHRN Testing can be customized if you would like to order a hearing-specific or vision-specific gene panel. Targeted familial testing is also available.

7 Specimen requirements Prenatal Please provide one of the following specimen types: Two confluent T-25 flasks of cultured cells from amniotic fluid or chorionic villi >4 mg of direct chorionic villi tissue 15 ml of direct amniotic fluid 5-10 ml of blood in an EDTA tube (lavender top) is required from each biological parent. Parental blood samples may be used for maternal cell contamination studies or confirmation studies. Please note: Prenatal analysis will only be performed for known parental variants Whole blood Newborn or child One 2 ml EDTA tube (lavender top) or one 2 ml ACD-A or ACD-B tube (yellow top) from the patient One 5-10 ml EDTA tube (lavender top) or one 5-10 ml ACD-A or ACD-B tube (yellow top) is also recommended from each biological parent Adult Two 5-10 ml EDTA tubes (lavender top) or two 5-10 ml ACD-A or ACD-B tubes (yellow top) from the patient One 5-10 ml EDTA tube (lavender top) or one 5-10 ml ACD-A or ACD-B tube (yellow top) is also recommended from each biological parent Extracted DNA A minimum of 10 µl DNA ( ng/µl) is required for testing. 20 µl DNA ( ng/µl) is recommended Saliva Saliva specimens are accepted upon request. Please contact our laboratory to obtain saliva kits Saliva samples should be collected in Oragene DNA (OG-500) kits by DNA Genotek Shipping requirements Tubes of blood, cultured cells, direct chorionic villus sampling, and direct amniotic fluid should be stored and shipped at room temperature or refrigerated. Do not freeze specimens Please ship specimens same day or overnight to: 1428 Madison Ave, Atran Bldg, Rm 2-25, New York, NY Turnaround time Prenatal: 7-10 business days from receipt of specimen Pediatric or adult: 3-4 weeks from receipt of specimen

8 Advanced genomic technology for highly-accurate results Next-generation sequencing (NGS) technology is ideal for diagnostic testing of these disorders due to the extreme locus heterogeneity and phenotype overlap of the genes involved. Our customizable targeted NGS panel uses Agilent SureSelect target enrichment and Illumina HiSeq sequencing. The sensitivity of this panel is estimated at 99% for single-base substitutions. If indicated, Sanger sequencing may be performed in both directions using BigDye Terminator chemistry with the ABI 3730 DNA analyzer with target specific amplicons. It may also be used to supplement specific guaranteed target regions that fail NGS sequencing or as a confirmatory method for NGS positive results. NGS technology may not detect all small insertions or deletions. Additionally, it is not diagnostic for large duplications or deletions, repeat expansions, and structural genomic variation. Therefore, multiplex ligation-dependent probe amplification (MLPA) and oligonucleotide array comparative genomic hybridization (acgh) are available for this test for deletion/duplication analysis. MLPA copy number analysis is available for the DFNB1 (GJB2/GJB6) locus, OTOA, and STRC. This MLPA testing is approximately 99% accurate. The customized oligonucleotide microarray is a highly-targeted, exon-focused array capable of detecting microdeletions and microduplications at a much higher resolution than traditional acgh methods. The sensitivity of the acgh assay is estimated to be greater than 99% for medically-relevant microdeletions and microduplications in the exonic regions of 304 genes. Please contact for additional information or questions about this test. NGS technology may not detect all small insertions/deletions and is not diagnostic for large duplications/deletions, repeat expansions, and structural genomic variation. This test will only detect variants within the exons and the intron-exon boundaries of the target genes. The following regions were excluded from NGS analysis due to limitations of NGS: ESPN exons 3 and 7, OTOA exons 19 to 27, RP1L1 exon 4, STRC exons 1 to 29, and TRIOBP exon 7. NGS of the MT-RNR1 gene is limited to targeted variant analysis of variants chrm:1494c>t and chrm:1555a>g. acgh technology cannot detect balanced rearrangements or imbalances that are below the resolution of this array. This technology will also not detect point mutations or small insertion/deletions below this array s resolution. Copy number variation of MT-RNR1, P2RX2, STRC, and RAB28 will not be reported using acgh. sema4.com 2018 Mount Sinai Genomics, Inc. D/B/A Sema4. All rights reserved. LLP0204GE0418