Examines genetic causes of craniofacial conditions; 45 genes included 

• Genes: ALPL, ALX1, ALX3, ALX4, CDC45, CYP26B1, DHODH, EFNB1, EFTUD2, ERF, FBN1, FGFR1, FGFR2, FGFR3, FREM1, GLI3, IFT122, IFT43, IHH, IL11RA, KRAS, MASP1, MEGF8, MSX2, P4HB, PHF6, PHF8, POLR1C, POLR1D, POR, RAB23, RECQL4, RSPRY1, SEC24D, SKI, TCF12, TCOF1, TGFBR1, TGFBR2, TMCO1, TWIST1, WDR19, WDR35, ZIC1, ZSWIM6

Test Information 

• Test Method: DNA extraction (if applicable) and ultrasonic fragmentation; targeted capture of the coding regions and intron/exon boundaries of protein coding RefSeq genes using a TWIST custom exome library capture; next generation sequencing (NGS) on an Illumina NovaSeq instrument; alignment to the human reference genome (GRCh37/hg19) using the Burrows-Wheeler Aligner (bwa); variant calling using GATK and detection of exonic deletions and duplications using ExomeDepth; Sanger sequencing to confirm low quality and/or complex indel variants related to the specified phenotype(s); Review of sequence and dosage data for the specified genes by multiple staff members; Variant classification following ACMG criteria (if applicable). Bioinformatic analysis was performed using DDL pipeline DDL.TWISTExome.v1.2020_12_22 and DDL.TWIST.Exome.Dosage.v1.2020_12_20.
• Clinical Utility: Discrimination between multiple heritable disorders associated with craniofacial conditions; identification of causative mutations in complex cases that span multiple phenotypes; facilitation of targeted carrier testing of relatives of proband and/or predictive prenatal testing.
• Clinical Sensitivity: The detection rate for the CraniofacialZoom panel is undetermined at this point, due to ongoing research in the field.
• Analytical Sensitivity: Sequencing: >94% for single nucleotide and >76% for small insertion/deletion variants for the nucleotides evaluated. Exonic deletions/duplications: >97% for unique regions of the genome. This test is not validated to identify small deletions/insertions of greater than 20bp, exonic deletions and duplications in pseudogenes or other repetitive regions of the genome (e.g. segmental duplications), nucleotide repeat expansions, mitochondrial DNA variants or mosaicism. Disease-associated variants in regions that are not captured and/or sufficiently sequenced will not be detected by this assay.

Examines genetic causes of Fanconi anemia; 22 genes included 

• Genes: BRCA1, BRCA2, BRIP1, ERCC4, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MAD2L2, PALB2, RAD51, RAD51C, RFWD3, SLX4, UBE2T, XRCC2

Test Information

• Test Method: DNA extraction (if applicable) and ultrasonic fragmentation; targeted capture of the coding regions and intron/exon boundaries of protein coding RefSeq genes using a TWIST custom exome library capture; next generation sequencing (NGS) on an Illumina NovaSeq instrument; alignment to the human reference genome (GRCh37/hg19) using the Burrows-Wheeler Aligner (bwa); variant calling using GATK and detection of exonic deletions and duplications using ExomeDepth; Sanger sequencing to confirm low quality and/or complex indel variants related to the specified phenotype(s); Review of sequence and dosage data for the specified genes by multiple staff members; Variant classification following ACMG criteria (if applicable). Bioinformatic analysis was performed using DDL pipeline DDL.TWISTExome.v1.2020_12_22 and DDL.TWIST.Exome.Dosage.v1.2020_12_20.
• Clinical Utility: Discrimination between multiple heritable etiologies of Fanconi anemia; identification of causative mutations in complex cases that span multiple phenotypes; facilitation of targeted carrier testing of relatives of proband and/or predictive prenatal testing.
• Clinical Sensitivity: The detection rate for the FancZoom panel is undetermined at this point, due to ongoing research in the field.
• Analytical Sensitivity: Sequencing: >94% for single nucleotide and >76% for small insertion/deletion variants for the nucleotides evaluated. Exonic deletions/duplications: >97% for unique regions of the genome. This test is not validated to identify small deletions/insertions of greater than 20bp, exonic deletions and duplications in pseudogenes or other repetitive regions of the genome (e.g. segmental duplications), nucleotide repeat expansions, mitochondrial DNA variants or mosaicism. Disease-associated variants in regions that are not captured and/or sufficiently sequenced will not be detected by this assay.

Examines genetic causes of anemia and other red blood cell disorders; 96 genes included

• Congenital dyserythropoietic anemia: ALAS2, CAD, CDAN1, CDIN1, GATA1, KIF23, KLF1, LPIN2, RACGAP1, SEC23B, VPS4A; Preliminary evidence: COX4I2, MVK, PARP4, PRDX2

• Erythrocytosis: BPGM, EGLN1, EPAS1, EPO, EPOR, HBA1, HBA2, HBB, JAK2, VHL; Preliminary evidence: SH2B3

• Erythropoietic porphyria: ALAS2, FECH, GATA1, UROS

• Hemoglobinopathy: HBA1, HBA2, HBB, HBD

• Megaloblastic anemia: ABCD4, AMN, CUBN, DHFR, HCFC1, HPRT1, LMBRD1, MMACHC, MMADHC, MTHFD1, MTR, MTRR, SLC19A2, SLC46A1, TCN2, UMPS; Preliminary evidence: SLC19A1

• RBC enzymopathy / Hemolytic anemia: AK1, ALDOA, CYB5R3, G6PD, GCLC, GPI, GSR, GSS, HK1, HMOX1, NT5C3A, PC, PFKM, PGK1, PKLR, TPI1; Preliminary evidence: GPX1

• RBC membranopathy / Hemolytic anemia: ABCG5, ABCG8, ANK1, ATP11C, COL4A1, EPB41, EPB42, KCNN4, PIEZO1, RHAG, SLC2A1, SLC4A1, SPTA1, SPTB, XK; Preliminary evidence: GYPC

• Sideroblastic anemia: ABCB7, ALAS2, FECH, GLRX5, HSPA9, LARS2, NDUFB11, PUS1, SLC19A2, SLC25A38, TRNT1, YARS2; Preliminary evidence: HSCB

• Other anemias: ATRX, CP, MTTP, SLC11A2, SLC40A1, TF, TMPRSS6

Test Information

• Test Method: DNA extraction (if applicable) and ultrasonic fragmentation; targeted capture of the coding regions and intron/exon boundaries of protein coding RefSeq genes using a TWIST custom exome library capture; next generation sequencing (NGS) on an Illumina NovaSeq instrument; alignment to the human reference genome (GRCh37/hg19) using the Burrows-Wheeler Aligner (bwa); variant calling using GATK and detection of exonic deletions and duplications using ExomeDepth; Sanger sequencing to confirm low quality and/or complex indel variants related to the specified phenotype(s); Review of sequence and dosage data for the specified genes by multiple staff members; Variant classification following ACMG criteria (if applicable). Bioinformatic analysis was performed using DDL pipeline DDL.TWISTExome.v1.2020_12_22 and DDL.TWIST.Exome.Dosage.v1.2020_12_20.
• Clinical Utility: Discrimination between multiple heritable disorders associated with anemia and other RBC disorders; identification of causative mutations in complex cases that span multiple phenotypes; facilitation of targeted carrier testing of relatives of proband and/or predictive prenatal testing.
• Clinical Sensitivity: The detection rate for the HemeZoom panel is undetermined at this point, due to ongoing research in the field.
• Analytical Sensitivity: Sequencing: >94% for single nucleotide and >76% for small insertion/deletion variants for the nucleotides evaluated. Exonic deletions/duplications: >97% for unique regions of the genome. This test is not validated to identify small deletions/insertions of greater than 20bp, exonic deletions and duplications in pseudogenes or other repetitive regions of the genome (e.g. segmental duplications) including the alpha and beta hemoglobin loci, nucleotide repeat expansions, mitochondrial DNA variants or mosaicism. Disease-associated variants in regions that are not captured and/or sufficiently sequenced will not be detected by this assay.

Examines genetic causes of decreased bone mineral density; 51 genes included 

• Conditions Included: 
  • *Fragile bones
  • *Osteopenia

• Genes: ALPL, ANKH, ANO5, ATP6V0A2, B4GALT7, BMP1, CASR, CLCN5, COL1A1, COL1A2, CREB3L1, CRTAP, CYP27B1, DMP1, ENPP1, FGF23, FKBP10, GNAS, GORAB, IFIH1, IFITM5, LMNA, LRP5, MAFB, MMP2, NOTCH2, P3H1, P4HB, PHEX, PLOD2, PLS3, PPIB, PTH1R, PYCR1, RUNX2, SEC24D, SERPINF1, SERPINH1, SLC34A3, SP7, SPARC, TMEM38B, TNFRSF11A, TNFRSF11B, TREM2, TRPV6, TYROBP, WNT1, XYLT2, ZMPSTE24

Test Information

• Test Method: DNA extraction (if applicable) and ultrasonic fragmentation; targeted capture of the coding regions and intron/exon boundaries of protein coding RefSeq genes using a TWIST custom exome library capture; next generation sequencing (NGS) on an Illumina NovaSeq instrument; alignment to the human reference genome (GRCh37/hg19) using the Burrows-Wheeler Aligner (bwa); variant calling using GATK and detection of exonic deletions and duplications using ExomeDepth; Sanger sequencing to confirm low quality and/or complex indel variants related to the specified phenotype(s); Review of sequence and dosage data for the specified genes by multiple staff members; Variant classification following ACMG criteria (if applicable). Bioinformatic analysis was performed using DDL pipeline DDL.TWISTExome.v1.2020_12_22 and DDL.TWIST.Exome.Dosage.v1.2020_12_20.
• Clinical Utility: Discrimination between multiple heritable disorders associated with decreased bone mineral density; identification of causative mutations in complex cases that span multiple phenotypes; facilitation of targeted carrier testing of relatives of proband and/or predictive prenatal testing.
• Clinical Sensitivity: The detection rate for the LowBoneDensityZoom panel is undetermined at this point, due to ongoing research in the field.
• Analytical Sensitivity: Sequencing: >94% for single nucleotide and >76% for small insertion/deletion variants for the nucleotides evaluated. Exonic deletions/duplications: >97% for unique regions of the genome. This test is not validated to identify small deletions/insertions of greater than 20bp, exonic deletions and duplications in pseudogenes or other repetitive regions of the genome (e.g. segmental duplications), nucleotide repeat expansions, mitochondrial DNA variants or mosaicism. Disease-associated variants in regions that are not captured and/or sufficiently sequenced will not be detected by this assay.

Examines genetic causes of bone marrow failure; 149 genes included 

• Conditions Included:
  • *Thrombocytopenia
  • *MDS and acute leukemia
  • *Short telomere syndromes
  • *Diamond-Blackfan anemia and DBA-like hypoplastic anemias
  • *Fanconi anemia
  • *Severe congenital neutropenia
  • *Sideroblastic anemia
  • *Familial MPN
  • *Additional genes

• Genes: ABCB7, ACD, ACTN1, ADA2, ALAS2, ANKRD26, ATG2B, ATM, BLM, BPGM, BRCA1, BRCA2, BRIP1, CBL, CDIN1, CEBPA, CHEK2, CSF3R, CTC1, CXCR4, CYCS, DDX41, DKC1, DNAJC21, EFL1, EGLN1, EGLN2, ELANE, EPAS1, EPCAM, EPO, EPOR, ERCC4, ERCC6L2, ETV6, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FLI1, FLNA, FYB1, G6PC3, GATA1, GATA2, GFI1, GFI1B, GLRX5, GP1BA, GP1BB, GP9, HAX1, HBB, HOXA11, IKZF1, ITGA2B, ITGB3, JAGN1, JAK2, KRAS, LIG4, LYST, MAD2L2, MLH1, MPL, MSH2, MSH6, MYH9, MYSM1, NAF1, NBEAL2, NBN, NF1, NHP2, NOP10, NRAS, PALB2, PARN, PAX5, PMS2, POT1, PRKACG, PTPN11, PUS1, RAB27A, RAD51, RAD51C, RBBP6, RBM8A, RFWD3, RPL11, RPL15, RPL18, RPL26, RPL27, RPL31, RPL35, RPL35A, RPL5, RPS10, RPS15A, RPS17, RPS19, RPS24, RPS26, RPS27, RPS28, RPS29, RPS7, RTEL1, RUNX1, SAMD9, SAMD9L, SBDS, SH2B3, SLC19A2, SLC25A38, SLC37A4, SLFN14, SLX4, SRC, SRP54, SRP72, STN1, TAFAZZIN, TERC, TERF2IP, TERT, THPO, TINF2, TP53, TRNT1, TSR2, TUBB1, UBE2T, USB1, VHL, VPS13B, VPS45, VWF, WAS, WRAP53, WRN, XPC, XRCC2, YARS2, ZCCHC8; Preliminary evidence: FAAP100, TCIRG1

Test Information  

• Test Method: DNA extraction (if applicable) and ultrasonic fragmentation; targeted capture of the coding regions and intron/exon boundaries of protein coding RefSeq genes using a TWIST custom exome library capture; next generation sequencing (NGS) on an Illumina NovaSeq instrument; alignment to the human reference genome (GRCh37/hg19) using the Burrows-Wheeler Aligner (bwa); variant calling using GATK and detection of exonic deletions and duplications using ExomeDepth; Sanger sequencing to confirm low quality and/or complex indel variants related to the specified phenotype(s); Review of sequence and dosage data for the specified genes by multiple staff members; Variant classification following ACMG criteria (if applicable). Bioinformatic analysis was performed using DDL pipeline DDL.TWISTExome.v1.2020_12_22 and DDL.TWIST.Exome.Dosage.v1.2020_12_20.
• Clinical Utility: Discrimination between multiple heritable causes of bone marrow failure; identification of causative mutations in complex cases that span multiple phenotypes; facilitation of targeted carrier or presymptomatic testing of relatives of proband and/or predictive prenatal testing.
• Clinical Sensitivity: The detection rate for the MarrowZoom panel is undetermined at this point, due to ongoing research in the field.
• Analytical Sensitivity: Sequencing: >94% for single nucleotide and >76% for small insertion/deletion variants for the nucleotides evaluated. Exonic deletions/duplications: >97% for unique regions of the genome. This test is not validated to identify small deletions/insertions of greater than 20bp, exonic deletions and duplications in pseudogenes or other repetitive regions of the genome (e.g. segmental duplications), nucleotide repeat expansions, mitochondrial DNA variants or mosaicism. Disease-associated variants in regions that are not captured and/or sufficiently sequenced will not be detected by this assay.

Examines genetic causes of neuromuscular disorders; 251 genes included 

• Myopathy: ACTA1, ADSS1, AGL, AGRN, ALG14, ALG2, AMPD1, ANO5, ASAH1, ATP2A1, B3GALNT2, B4GAT1, BAG3, BIN1, BVES, CACNA1S, CAPN1, CAPN3, CASQ1, CAV3, CAVIN1, CCDC78, CFL2, CHAT, CHKB, CHRNA1, CHRNB1, CHRND, CHRNE, CLCN1, CNTN1, COL12A1, COL13A1, COL6A1, COL6A2, COL6A3, COLQ, CPT2, CRPPA, CRYAB, DAG1, DCTN1, DES, DMD, DNAJB6, DNM2, DOK7, DPAGT1, DPM1, DPM2, DPM3, DYSF, EMD, FBXO38, FHL1, FKBP14, FKRP, FKTN, FLNC, GAA, GARS1, GBE1, GFPT1, GLE1, GMPPB, GNE, GYS1, HNRNPA1, HNRNPA2B1, HNRNPDL, ISCU, ISPD, ITGA7, KBTBD13, KCNJ2, KLHL40, KLHL41, KY, LAMA2, LAMP2, LARGE1, LDB3, LIMS2, LMNA, LMOD3, LRP4, MATR3, MEGF10, MICU1, MTM1, MUSK, MYH2, MYH3, MYH7, MYO18B, MYOT, MYPN, NALCN, NEB, ORAI1, PAX7, PFKM, PLEC, PMM2, PNPLA2, POMGNT1, POMGNT2, POMK, POMT1, POMT2, PREPL, PYGM, PYROXD1, RAPSN, RXYLT1, RYR1, SCN4A, SELENON, SETX, SGCA, SGCB, SGCD, SGCE, SGCG, SIL1, SLC18A3, SLC52A2, SLC5A7, SNAP25, SPEG, SQSTM1, STAC3, STIM1, SYNE1, SYNE2, SYT2, TAFAZZIN, TCAP, TIA1, TMEM43, TNNI2, TNNT1, TNPO3, TOR1AIP1, TPM2, TPM3, TRAPPC11, TRIM32, TRIP4, TTN, UBA1, VCP, VMA21, VRK1

• Charcot-Marie-Tooth disease: AARS1, AIFM1, ATL1, ATP7A, BICD2, BSCL2, DNAJB2, DNM2, DNMT1, DYNC1H1, EGR2, ELP1, FGD4, FIG4, GAN, GARS1, GDAP1, GJB1, GLA, GNB4, HARS1, HINT1, HSPB1, HSPB8, IGHMBP2, INF2, KIF1A, KIF5A, LITAF, LMNA, LRSAM1, MFN2, MME, MORC2, MPZ, MTMR2, NDRG1, NEFL, NGF, NTRK1, PHKA1, PLEKHG5, PMP22, PRDM12, PRPS1, PRX, RAB7A, REEP1, RETREG1, SBF1, SBF2, SCN11A, SCN9A, SEPTIN9, SH3TC2, SLC12A6, SLC52A2, SLC52A3, SPTLC1, SPTLC2, TFG, TRIM2, TRPV4, TTR, WNK1, YARS1

• Hereditary spastic paraplegia: ABCD1, ALDH18A1, ALS2, AP4B1, AP4E1, AP4M1, AP4S1, AP5Z1, ATL1, ATP13A2, B4GALNT1, BSCL2, CYP2U1, CYP7B1, DDHD1, DDHD2, ERLIN2, FA2H, GBA2, GJC2, HSPD1, KIF1A, KIF1C, KIF5A, L1CAM, MTRFR, NIPA1, NT5C2, PLP1, PNPLA6, REEP1, RTN2, SACS, SLC16A2, SLC33A1, SPART, SPAST, SPG11, SPG21, SPG7, TECPR2, TFG, VPS37A, WASHC5, ZFYVE26

Test Information

• Test Method: DNA extraction (if applicable) and ultrasonic fragmentation; targeted capture of the coding regions and intron/exon boundaries of protein coding RefSeq genes using a TWIST custom exome library capture; next generation sequencing (NGS) on an Illumina NovaSeq instrument; alignment to the human reference genome (GRCh37/hg19) using the Burrows-Wheeler Aligner (bwa); variant calling using GATK and detection of exonic deletions and duplications using ExomeDepth; Sanger sequencing to confirm low quality and/or complex indel variants related to the specified phenotype(s); Review of sequence and dosage data for the specified genes by multiple staff members; Variant classification following ACMG criteria (if applicable). Bioinformatic analysis was performed using DDL pipeline DDL.TWISTExome.v1.2020_12_22 and DDL.TWIST.Exome.Dosage.v1.2020_12_20.
• Clinical Utility: Discrimination between multiple heritable disorders involving the neuromuscular system; identification of causative mutations in complex cases that span multiple phenotypes; facilitation of targeted carrier or presymptomatic testing of relatives of proband and/or predictive prenatal testing.
• Clinical Sensitivity: The detection rate for the NeuromuscularZoom panel is undetermined at this point, due to ongoing research in the field.
• Analytical Sensitivity: Sequencing: >94% for single nucleotide and >76% for small insertion/deletion variants for the nucleotides evaluated. Exonic deletions/duplications: >97% for unique regions of the genome. This test is not validated to identify small deletions/insertions of greater than 20bp, exonic deletions and duplications in pseudogenes or other repetitive regions of the genome (e.g. segmental duplications), nucleotide repeat expansions, mitochondrial DNA variants or mosaicism. Disease-associated variants in regions that are not captured and/or sufficiently sequenced will not be detected by this assay.

Examines genetic causes of diffuse lung disease; 121 genes included

• Mucociliary disorders: CCDC103, CCDC39, CCDC40, CCDC65, CCNO, CFAP298, CFAP300, CFTR, DNAAF1, DNAAF11, DNAAF2, DNAAF3, DNAAF4, DNAAF5, DNAAF6, DNAH1, DNAH11, DNAH5, DNAH8, DNAH9, DNAI1, DNAI2, DNAJB13, DNAL1, DRC1, FOXJ1, GAS2L2, GAS8, HYDIN, LRRC56, MCIDAS, NEK10, NME8, ODAD1, ODAD2, ODAD3, ODAD4, OFD1, RPGR, RSPH1, RSPH3, RSPH4A, RSPH9, SCNN1A, SCNN1B, SCNN1G, SPAG1, SPZ1, TTC12, ZMYND10

• Interstitial lung disease: ABCA3, AP3B1, COPA, CSF2RA, CSF2RB, DKC1, ELMOD2, FLCN, FLNA, FOXF1, GATA2, GBA, HPS1, HPS4, IDUA, MARS, NAF1, NF1, NKX2-1, NPC2, OAS1, PARN, RAB5B, RTEL1, SFTPA1, SFTPA2, SFTPB, SFTPC, SLC34A2, SLC7A7, SMPD1, STAT3, TBX4, TERC, TERT, TINF2, TMEM173, TSC1, TSC2, ZCCHC8

• Pulmonary vascular disorders: ABCC8, ABCC9, ACVRL1, ARHGAP31, ATP13A3, BMPR2, CAV1, DLL4, DOCK6, EIF2AK4, ENG, EOGT, FOXF1, FOXRED1, GDF2, GGCX, KCNK3, KDR, NFU1, NOTCH1, RASA1, RBPJ, SARS2, SMAD4, SMAD9, SOX17, TBX4, TET2, TMEM70; Preliminary evidence: AQP1, BMP10, BMPR1A, BMPR1B, COX5A, FBLN2, KCNJ8 , KLF2, KLK1, NOTCH3, PDGFD, SMAD1

Test Information  

• Test Method: DNA extraction (if applicable) and ultrasonic fragmentation; targeted capture of the coding regions and intron/exon boundaries of protein coding RefSeq genes using a TWIST custom exome library capture; next generation sequencing (NGS) on an Illumina NovaSeq instrument; alignment to the human reference genome (GRCh37/hg19) using the Burrows-Wheeler Aligner (bwa); variant calling using GATK and detection of exonic deletions and duplications using ExomeDepth; Sanger sequencing to confirm low quality and/or complex indel variants related to the specified phenotype(s); Review of sequence and dosage data for the specified genes by multiple staff members; Variant classification following ACMG criteria (if applicable). Bioinformatic analysis was performed using DDL pipeline DDL.TWISTExome.v1.2020_12_22 and DDL.TWIST.Exome.Dosage.v1.2020_12_20.
• Clinical Utility: Discrimination between multiple heritable disorders that can cause diffuse lung disease; identification of causative variants in complex cases that span multiple phenotypes; facilitation of targeted carrier or presymptomatic testing of relatives of proband and/or predictive prenatal testing.
• Clinical Sensitivity: The detection rate for the PulmZoom panel is undetermined at this point, due to ongoing research in the field.
• Analytical Sensitivity: Sequencing: >94% for single nucleotide and >76% for small insertion/deletion variants for the nucleotides evaluated. Exonic deletions/duplications: >97% for unique regions of the genome. This test is not validated to identify small deletions/insertions of greater than 20bp, exonic deletions and duplications in pseudogenes or other repetitive regions of the genome (e.g. segmental duplications), nucleotide repeat expansions, mitochondrial DNA variants or mosaicism. Disease-associated variants in regions that are not captured and/or sufficiently sequenced will not be detected by this assay.

Examines genetic causes of renal disease; 337 genes included

Glomerular diseases and complement genes: ACE, ACTN4, ADAMTS13, ALG1, ALMS1, ANLN, APOE, APOL1, AQP2, ARHGAP24, ARHGDIA, AVPR2, C1QA, C1QB, C1QC, C1R, C1S, C2, C2CD3, C3, C3AR1, C4A, C4B, C4BPA, C4BPB, C5, C5AR1, C6, C7, C8A, C8B, C8G, C9, CD151, CD2AP, CD46, CD55, CD59, CD93, CFB, CFD, CFH, CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, CFI, CFP, CLU, COL4A1, COL4A3, COL4A4, COL4A5, COL4A6, COQ2, COQ6, COQ8B, CR1, CR2, CRB2, CUBN, DGKE, ELANE, EMP2, ENPP1, F2, FAT1, FCN1, FCN2, FCN3, FGA, FN1, GLA, GLIS3, GREM1, HNF1B, HNF4A, INF2, ITGA3, ITGAM, ITGAX, ITGB2, ITGB4, LAMB2, LMX1B, MBL2, MEFV, MMACHC, MYH9, MYO1E, NPHS1, NPHS2, NUP107, NUP205, NUP93, OCRL, PAX2, PDSS2, PLCE1, PLCG2, PODXL, REN, SCARB2, SERPING1, SGPL1, SLC17A5, SLC5A1, SLC5A2, SMARCAL1, THBD, TNFRSF1A, TRPC6, VEGFA, VSIG4, VTN, WDR73, WT1

Disorders of ion transport, nephrolithiasis, and nephrocalcinosis: ACE, ADCY10, AGT, AGTR1, AGXT, APRT, AQP2, ATP6V0A4, ATP6V1B1, ATP7B, AVPR2, BSND, CA2, CACNA1D, CACNA1H, CACNA1S, CASR, CDC73, CLCN5, CLCNKA, CLCNKB, CLDN16, CLDN19, CNNM2, CUL3, CYP11B1, CYP11B2, CYP24A1, DMP1, EGF, EHHADH, ENPP1, FAH, FGF23, FXYD2, GATA3, GRHPR, HNF4A, HOGA1, HPRT1, HSD11B2, KCNJ1, KCNJ10, KCNJ2, KCNJ5, KLHL3, LRP5, MAGED2, NEDD4L, NHERF1, NOTCH2, NR3C2, OCRL, PHEX, PLG, REN, SARS2, SCN4A, SCNN1A, SCNN1B, SCNN1G, SLC12A1, SLC12A3, SLC22A12, SLC2A9, SLC34A1, SLC34A3, SLC3A1, SLC4A1, SLC4A4, SLC7A9, TRPM6, VDR, WNK1, WNK4, XDH

CAKUT, ciliopathies, tubulointerstitial diseases, and other: ACE, AGT, AGTR1, AHI1, ALG9, ALMS1, ANKS6, APOA1, ARL13B, ARL6, B2M, B9D1, B9D2, BBIP1, BBS1, BBS10, BBS12, BBS2, BBS4, BBS5, BBS7, BBS9, BICC1, BMP4, BMPER, CC2D2A, CDC73, CEP104, CEP120, CEP164, CEP290, CEP41, CEP83, CFAP418, CHD1L, CHD7, CLCN5, COLEC10, COLEC11, COQ8A, CPLANE1, CREBBP, CSPP1, CTNS, DACH1, DCDC2, DHCR7, DHTKD1, DLC1, DLG1, DNAJB11, DSTYK, DYNC2H1, E2F3, EYA1, FAH, FAN1, FAT1, FGA, FGF20, FGFR1, FOXP1, FRAS1, FREM1, FREM2, GANAB, GATA3, GDNF, GLI3, GLIS2, GLIS3, GPC3, GRIP1, GSN, HNF1B, IFT122, IFT140, IFT172, IFT27, IFT43, IFT74, IFT80, INPP5E, INVS, IQCB1, ITGA8, ITGB2, JAG1, KCTD1, KATNIP, KIAA0586, KIF12, KIF14, KIF7, LMNA, LRP5, LYZ, LZTFL1, MASP1, MASP2, MEFV, MKKS, MKS1, NEIL1, NEK1, NEK8, NLRP3, NOTCH2, NPHP1, NPHP3, NPHP4, OFD1, PAX2, PBX1, PDE6D, PKD1, PKD2, PKHD1, PMM2, REN, RET, ROBO2, RPGRIP1L, SALL1, SALL4, SARS2, SDCCAG8, SEC61A1, SEMA3E, SIX1, SIX2, SIX5, SLC2A2, SLC41A1, SLIT2, SOX17, SRGAP1, TBX18, TCTN1, TCTN2, TCTN3, TFAP2A, TMEM107, TMEM138, TMEM216, TMEM231, TMEM237, TMEM67, TNXB, TRAP1, TRIM32, TSC1, TSC2, TTC21B, TTC8, TTR, UMOD, UPK3A, UPK3B, VHL, VIPAS39, VPS33B, WDPCP, WDR19, WDR35, WNT4, WT1, XPNPEP3, ZMPSTE24, ZNF423

Test Method

• Test Method: DNA extraction (if applicable) and ultrasonic fragmentation; targeted capture of the coding regions and intron/exon boundaries of protein coding RefSeq genes using a TWIST custom exome library capture; next generation sequencing (NGS) on an Illumina NovaSeq instrument; alignment to the human reference genome (GRCh37/hg19) using the Burrows-Wheeler Aligner (bwa); variant calling using GATK and detection of exonic deletions and duplications using ExomeDepth; Sanger sequencing to confirm low quality and/or complex indel variants related to the specified phenotype(s); Review of sequence and dosage data for the specified genes by multiple staff members; Variant classification following ACMG criteria (if applicable). Bioinformatic analysis was performed using DDL pipeline DDL.TWISTExome.v1.2020_12_22 and DDL.TWIST.Exome.Dosage.v1.2020_12_20.
• Clinical Utility: Discrimination between multiple heritable etiologies of renal disease; identification of causative variants in complex cases that span multiple phenotypes; facilitation of targeted carrier or presymptomatic testing of relatives of proband and/or predictive prenatal testing.
• Clinical Sensitivity: The detection rate for the RenalZoom panel is undetermined at this point, due to ongoing research in the field.
• Analytical Sensitivity: Sequencing: >94% for single nucleotide and >76% for small insertion/deletion variants for the nucleotides evaluated. Exonic deletions/duplications: >97% for unique regions of the genome. This test is not validated to identify small deletions/insertions of greater than 20bp, exonic deletions and duplications in pseudogenes or other repetitive regions of the genome (e.g. segmental duplications), nucleotide repeat expansions, mitochondrial DNA variants or mosaicism. Disease-associated variants in regions that are not captured and/or sufficiently sequenced will not be detected by this assay.

Examines genetic causes of short-rib polydactyly and skeletal ciliopathies; 23 genes included

• Conditions Included:
  • *Short-rib polydactyly
  • *Skeletal ciliopathies 

• Genes: CEP120, CSPP1, DYNC2H1, EVC, EVC2, FGFR1, FGFR2, FGFR3, IFT122, IFT140, IFT172, IFT80, KIAA0586, NEK1, PAPSS2, SLC26A2, SOX9, TCTN3, TTC21B, WDR19, WDR34, WDR35, WDR60

Test Information

• Test Method: DNA extraction (if applicable) and ultrasonic fragmentation; targeted capture of the coding regions and intron/exon boundaries of protein coding RefSeq genes using a TWIST custom exome library capture; next generation sequencing (NGS) on an Illumina NovaSeq instrument; alignment to the human reference genome (GRCh37/hg19) using the Burrows-Wheeler Aligner (bwa); variant calling using GATK and detection of exonic deletions and duplications using ExomeDepth; Sanger sequencing to confirm low quality and/or complex indel variants related to the specified phenotype(s); Review of sequence and dosage data for the specified genes by multiple staff members; Variant classification following ACMG criteria (if applicable). Bioinformatic analysis was performed using DDL pipeline DDL.TWISTExome.v1.2020_12_22 and DDL.TWIST.Exome.Dosage.v1.2020_12_20.
• Clinical Utility: Discrimination between multiple heritable etiologies of short-rib polydactyly and skeletal ciliopathies; identification of causative mutations in complex cases that span multiple phenotypes; facilitation of targeted carrier testing of relatives of proband and/or predictive prenatal testing.
• Clinical Sensitivity: The detection rate for the SkeletalZoom panel is undetermined at this point, due to ongoing research in the field.
• Analytical Sensitivity: Sequencing: >94% for single nucleotide and >76% for small insertion/deletion variants for the nucleotides evaluated. Exonic deletions/duplications: >97% for unique regions of the genome. This test is not validated to identify small deletions/insertions of greater than 20bp, exonic deletions and duplications in pseudogenes or other repetitive regions of the genome (e.g. segmental duplications), nucleotide repeat expansions, mitochondrial DNA variants or mosaicism. Disease-associated variants in regions that are not captured and/or sufficiently sequenced will not be detected by this assay.

Examines genetic causes Stickler syndrome and 22q11 deletion syndrome; 10 genes and targeted analysis for 22q11 deletion included

• Genes: COL2A1, COL9A1, COL9A2, COL9A3, COL11A1, COL11A2, LOXL3, LRP2, VCAN, (TBX1 for dosage only)

Test Information

• Test Method: DNA extraction (if applicable) and ultrasonic fragmentation; targeted capture of the coding regions and intron/exon boundaries of protein coding RefSeq genes using a TWIST custom exome library capture; next generation sequencing (NGS) on an Illumina NovaSeq instrument; alignment to the human reference genome (GRCh37/hg19) using the Burrows-Wheeler Aligner (bwa); variant calling using GATK and detection of exonic deletions and duplications using ExomeDepth; Sanger sequencing to confirm low quality and/or complex indel variants related to the specified phenotype(s); Review of sequence and dosage data for the specified genes by multiple staff members; Variant classification following ACMG criteria (if applicable). Bioinformatic analysis was performed using DDL pipeline DDL.TWISTExome.v1.2020_12_22 and DDL.TWIST.Exome.Dosage.v1.2020_12_20.
• Clinical Utility: Discrimination between multiple heritable etiologies of Stickler syndrome and 22q11 deletion syndrome; identification of causative mutations in complex cases that span multiple phenotypes; facilitation of targeted carrier testing of relatives of proband and/or predictive prenatal testing.
• Clinical Sensitivity: The detection rate for the Skeletal22qZoom panel is undetermined at this point, due to ongoing research in the field.
• Analytical Sensitivity: Sequencing: >94% for single nucleotide and >76% for small insertion/deletion variants for the nucleotides evaluated. Exonic deletions/duplications: >97% for unique regions of the genome. This test is not validated to identify small deletions/insertions of greater than 20bp, exonic deletions and duplications in pseudogenes or other repetitive regions of the genome (e.g. segmental duplications), nucleotide repeat expansions, mitochondrial DNA variants or mosaicism. Disease-associated variants in regions that are not captured and/or sufficiently sequenced will not be detected by this assay.

Examines genetic causes of short telomere disorders; 15 genes included

• Genes: ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53, ZCCHC8

• Note: TeloZoom is an exome-based test. For Telomere Length Testing, please contact the Molecular Diagnostics Lab.           

Syndrome Information

• Clinical Description: Short telomere syndromes are a spectrum of disease phenotypes that result from variants in genes involved in telomere maintenance PMID 22965356. The most common clinical manifestations are listed here and they may co-occur in patients and affected families.

Idiopathic pulmonary fibrosis is an age-related disorder characterized by scarring of the lungs. It runs in families and ~20% of idiopathic pulmonary fibrosis patients have an affected first degree relative PMID 22079513. Other types of lung disease cluster in families with germline defects in telomere maintenance including non-specific interstitial pneumonitis, pleuroparenchymal fibroelastosis (PPFE), chronic hypersensitivity pneumonitis and emphysema PMID 17392301, PMID 29703687, PMID 25562321.

Liver disease may be a first manifestation of short telomere syndromes either as cirrhosis or hepatopulmonary syndrome PMID 19936245, PMID 26158642.

Bone marrow failure includes spectrum of failed hematopoiesis and includes isolated cytopenias, overt aplastic anemia as well as myelodysplastic syndrome.

Immunodeficiency may also be a manifestation of primary short telomere syndromes alone or in combination with bone marrow failure PMID 30179220. Hoyeraal-Hreidarsson syndrome (HHS) is a severe short telomere syndrome that is classically associated with immunodeficiency, colitis PMID 23279657, intrauterine growth restriction, microcephaly, and cerebellar hypoplasia.

Dyskeratosis congenita is a classic short telomere disorder characterized by characteristic mucocutaneous findings namely nail dystrophy, oral leukoplakia and skin hyperpigmentation. Revesz syndrome is a rare bilateral exudative retinopathy which has been seen in pediatric patients with short telomere syndromes including Hoyeraal-Hreidarsson syndrome.

Coats plus syndrome is rare and has distinguishing features from other short telomere syndromes such as intracranial calcifications. It is most commonly caused by biallelic variants in CTC1 PMID 22267198.

• Inheritance Pattern: Autosomal dominant, autosomal recessive, X-linked recessive, and de novo

• Genotype-Phenotype Correlation: Telomere length is the strongest predictor of disease phenotype as well as severity in this group of disorders PMID 29463756. Genetic anticipation may show evolving patterns of disease in autosomal dominant families with older generations affected by pulmonary disease and younger generations by bone marrow failure PMID 21436073. Some clinical phenotypes that have genotype correlations additionally include:
  • Hoyeraal-Hreidarsson syndrome is commonly caused by mutations in DKC1 or TINF2 but has also been reported with biallelic variants in TERT, RTEL1 and PARN PMID 25940403.
  • Revesz syndrome is often associated with variants in TINF2 PMID 18252230.
  • Biallelic variants in CTC1 usually manifest as Coats plus syndrome (intracranial calcifications, retinal exudates, osteopenia, gastrointestinal bleeding). CTC1 biallelic variants may also be seen in rare cases of isolated bone marrow failure PMID 22532422.

Reversion has been described in patients with TERC variants PMID 22341970 and in one adult with a TINF2 variant PMID 25539146. If a patient who meets diagnostic criteria for short telomere syndrome has a negative molecular testing, it might be beneficial to repeat the sequencing from a non-hematopoietic tissue (e.g. fibroblast).

Test Information

• Test Method: DNA extraction (if applicable) and ultrasonic fragmentation; targeted capture of the coding regions and intron/exon boundaries of protein coding RefSeq genes using a TWIST custom exome library capture; next generation sequencing (NGS) on an Illumina NovaSeq instrument; alignment to the human reference genome (GRCh37/hg19) using the Burrows-Wheeler Aligner (bwa); variant calling using GATK and detection of exonic deletions and duplications using ExomeDepth; Sanger sequencing to confirm low quality and/or complex indel variants related to the specified phenotype(s); Review of sequence and dosage data for the specified genes by multiple staff members; Variant classification following ACMG criteria (if applicable). Bioinformatic analysis was performed using DDL pipeline DDL.TWISTExome.v1.2020_12_22 and DDL.TWIST.Exome.Dosage.v1.2020_12_20.
• Clinical Utility: Discrimination of genetic causes of short telomere disorders; identification of causative variants in known or highly suspicious cases; facilitation of targeted testing of relatives of probands and/or predictive or prenatal testing.
• Clinical Sensitivity: Variants in telomerase and telomere maintenance genes manifest in a number of clinical presentations that span infancy to adulthood. Testing telomere length by flow cytometry and FISH can functionally identify some of these patients and may also predictive of the severity of disease PMID 21436073. Approximately, 30% of patients with familial forms of pulmonary fibrosis and telomere-related lung disease carry variants in telomerase and telomere maintenance PMID 25539146. In sporadic cases of idiopathic pulmonary fibrosis, an estimated 5% of patients carry a variant. For unselected patients with idiopathic pulmonary fibrosis (i.e. a mix of familial and sporadic disease) approximately 10% carry germline variants in the common telomere maintenance genes PMID 28099038. For patients with familial clustering of bone marrow failure and idiopathic pulmonary fibrosis, approximately 80% carry variants in telomere maintenance genes PMID 21436073. Variants in telomere-related genes are likely the most common cause of inherited forms of bone marrow failure PMID 29146883. Telomere-mediated disease may also more rarely manifest as classic dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome or other more rare phenotypes as aforementioned where the yield of identifying the short telomere defect by flowFISH (link) is high and for identifying a disease-causing variant up to 80%.

Telomere length testing by flowFISH is offered through the Molecular Diagnostics Laboratory.

• Analytical Sensitivity: Sequencing: >94% for single nucleotide and >76% for small insertion/deletion variants for the nucleotides evaluated. Exonic deletions/duplications: >97% for unique regions of the genome. This test is not validated to identify small deletions/insertions of greater than 20bp, exonic deletions and duplications in pseudogenes or other repetitive regions of the genome (e.g. segmental duplications), nucleotide repeat expansions, mitochondrial DNA variants or mosaicism. Disease-associated variants in regions that are not captured and/or sufficiently sequenced will not be detected by this assay.

Other testing relevant to the valuation of inherited pulmonary fibrosis: PulmZoom

Price: $5600.00

CPT Code: 81415

Test Information

• Test Method: DNA extraction (if applicable) and ultrasonic fragmentation; targeted capture of the coding regions and intron/exon boundaries of protein coding RefSeq genes using a TWIST custom exome library capture; next generation sequencing (NGS) on an Illumina NovaSeq instrument; alignment to the human reference genome (GRCh37/hg19) using the BurrowsWheeler Aligner (bwa); variant calling using GATK and detection of exonic deletions and duplications using ExomeDepth; mtDNA variant calling using GATK Mutect2 mitomode and detection of mtDNA deletions using eKLIPse; Sanger sequencing to confirm low quality and/or complex indel variants related to the specified phenotype(s); Review of sequence and dosage data for the specified genes by multiple staff members; Variant classification following ACMG criteria (if applicable). Bioinformatic analysis was performed using DDL pipeline DDL.TWISTExome.v1.2020_12_22, DDL.TWIST.Exome.Dosage.v1.2020_12_20 and DDL.TWISTExome.mtDNA.v1.2021_09_02.
• Clinical Sensitivity: The clinical sensitivity of this assay is dependent on the phenotypic information provided to the laboratory. A causative genetic variant is identified in approximately 20-30% of affected individuals (Farwell et al., 2015, PMID 25356970; Retterer et al., 2016, PMID 26633542; Yang et al., 2013, PMID 24088041). A causative genetic variant in mtDNA is identified in approximately 50-75% of adults and 10-20% of children diagnosed with a primary mitochondrial disorder (Zeviani et al. 2004 PMID 15358637, Schaefer et al. 2008 PMID 17886296, Koenig 2008 PMID 18410845, Poulton et al. 2017 PMID 28536827). Disease-associated variants in the ACMG list of secondary findings genes are identified in approximately 3.4% of individuals (Johnston et al. 2022, PMID 34906458). This test is only validated for inherited gene alterations associated with the specified phenotype(s).
• Analytical Sensitivity: Sequencing: >94% for single nucleotide and >76% for small insertion/deletion variants for the nucleotides evaluated. Exonic deletions/duplications: >97% for unique regions of the genome. mtDNA: >97% for single nucleotide variants and 75% for large deletions. The lower limit of detection for mtDNA SNV variants is 5% and for mtDNA large deletions is 10%. This test is not validated to identify small deletions/insertions of greater than 20bp, exonic deletions and duplications in pseudogenes or other repetitive regions of the genome (e.g. segmental duplications), nucleotide repeat expansions, mitochondrial copy number or mosaicism. Disease-associated variants in regions that are not captured and/or sufficiently sequenced will not be detected by this assay.
• ACMG Secondary Findings Genes (v3.2): ACTA2, ACTC1, ACVRL1, APC, APOB, ATP7B, BAG3, BMPR1A, BRCA1, BRCA2, BTD, CACNA1S, CALM1, CALM2, CALM3, CASQ2, COL3A1, DES, DSC2, DSG2, DSP, ENG, FBN1, FLNC, GAA, GLA, HFE, HNF1A, KCNH2, KCNQ1, LDLR, LMNA, MAX, MEN1, MLH1, MSH2, MSH6, MUTYH, MYBPC3, MYH11, MYH7, MYL2, MYL3, NF2, OTC, PALB2, PCSK9, PKP2, PMS2, PRKAG2, PTEN, RB1, RBM20, RET, RPE65, RYR1, RYR2, SCN5A, SDHAF2, SDHB, SDHC, SDHD, SMAD3, SMAD4, STK11, TGFBR1, TGFBR2, TMEM127, TMEM43, TNNC1, TNNI3, TNNT2, TP53, TPM1, TRDN, TSC1, TSC2, TTN (A-band truncating variants only), TTR, VHL, WT1

Price: $6350.00

CPT Code: 81415, 81416

Test Information

• Test Method: DNA extraction (if applicable) and ultrasonic fragmentation; targeted capture of the coding regions and intron/exon boundaries of protein coding RefSeq genes using a TWIST custom exome library capture; next generation sequencing (NGS) on an Illumina NovaSeq instrument; alignment to the human reference genome (GRCh37/hg19) using the BurrowsWheeler Aligner (bwa); variant calling using GATK and detection of exonic deletions and duplications using ExomeDepth; mtDNA variant calling using GATK Mutect2 mitomode and detection of mtDNA deletions using eKLIPse; Sanger sequencing to confirm low quality and/or complex indel variants related to the specified phenotype(s); Review of sequence and dosage data for the specified genes by multiple staff members; Variant classification following ACMG criteria (if applicable). Bioinformatic analysis was performed using DDL pipeline DDL.TWISTExome.v1.2020_12_22, DDL.TWIST.Exome.Dosage.v1.2020_12_20 and DDL.TWISTExome.mtDNA.v1.2021_09_02.
• Clinical Sensitivity: The clinical sensitivity of this assay is dependent on the phenotypic information provided to the laboratory. A causative genetic variant is identified in approximately 20-30% of affected individuals (Farwell et al., 2015, PMID 25356970; Retterer et al., 2016, PMID 26633542; Yang et al., 2013, PMID 24088041). A causative genetic variant in mtDNA is identified in approximately 50-75% of adults and 10-20% of children diagnosed with a primary mitochondrial disorder (Zeviani et al. 2004 PMID 15358637, Schaefer et al. 2008 PMID 17886296, Koenig 2008 PMID 18410845, Poulton et al. 2017 PMID 28536827). Disease-associated variants in the ACMG list of secondary findings genes are identified in approximately 3.4% of individuals (Johnston et al. 2022, PMID 34906458). This test is only validated for inherited gene alterations associated with the specified phenotype(s).
• Analytical Sensitivity: Sequencing: >94% for single nucleotide and >76% for small insertion/deletion variants for the nucleotides evaluated. Exonic deletions/duplications: >97% for unique regions of the genome. mtDNA: >97% for single nucleotide variants and 75% for large deletions. The lower limit of detection for mtDNA SNV variants is 5% and for mtDNA large deletions is 10%. This test is not validated to identify small deletions/insertions of greater than 20bp, exonic deletions and duplications in pseudogenes or other repetitive regions of the genome (e.g. segmental duplications), nucleotide repeat expansions, mitochondrial copy number or mosaicism. Disease-associated variants in regions that are not captured and/or sufficiently sequenced will not be detected by this assay.
• ACMG Secondary Findings Genes (v3.2): ACTA2, ACTC1, ACVRL1, APC, APOB, ATP7B, BAG3, BMPR1A, BRCA1, BRCA2, BTD, CACNA1S, CALM1, CALM2, CALM3, CASQ2, COL3A1, DES, DSC2, DSG2, DSP, ENG, FBN1, FLNC, GAA, GLA, HFE, HNF1A, KCNH2, KCNQ1, LDLR, LMNA, MAX, MEN1, MLH1, MSH2, MSH6, MUTYH, MYBPC3, MYH11, MYH7, MYL2, MYL3, NF2, OTC, PALB2, PCSK9, PKP2, PMS2, PRKAG2, PTEN, RB1, RBM20, RET, RPE65, RYR1, RYR2, SCN5A, SDHAF2, SDHB, SDHC, SDHD, SMAD3, SMAD4, STK11, TGFBR1, TGFBR2, TMEM127, TMEM43, TNNC1, TNNI3, TNNT2, TP53, TPM1, TRDN, TSC1, TSC2, TTN (A-band truncating variants only), TTR, VHL, WT1

Price: $7100.00

CPT Code: 81415, 81416

Test Information

• Test Method: DNA extraction (if applicable) and ultrasonic fragmentation; targeted capture of the coding regions and intron/exon boundaries of protein coding RefSeq genes using a TWIST custom exome library capture; next generation sequencing (NGS) on an Illumina NovaSeq instrument; alignment to the human reference genome (GRCh37/hg19) using the BurrowsWheeler Aligner (bwa); variant calling using GATK and detection of exonic deletions and duplications using ExomeDepth; mtDNA variant calling using GATK Mutect2 mitomode and detection of mtDNA deletions using eKLIPse; Sanger sequencing to confirm low quality and/or complex indel variants related to the specified phenotype(s); Review of sequence and dosage data for the specified genes by multiple staff members; Variant classification following ACMG criteria (if applicable). Bioinformatic analysis was performed using DDL pipeline DDL.TWISTExome.v1.2020_12_22, DDL.TWIST.Exome.Dosage.v1.2020_12_20 and DDL.TWISTExome.mtDNA.v1.2021_09_02.
• Clinical Sensitivity: The clinical sensitivity of this assay is dependent on the phenotypic information provided to the laboratory. A causative genetic variant is identified in approximately 20-30% of affected individuals (Farwell et al., 2015, PMID 25356970; Retterer et al., 2016, PMID 26633542; Yang et al., 2013, PMID 24088041). A causative genetic variant in mtDNA is identified in approximately 50-75% of adults and 10-20% of children diagnosed with a primary mitochondrial disorder (Zeviani et al. 2004 PMID 15358637, Schaefer et al. 2008 PMID 17886296, Koenig 2008 PMID 18410845, Poulton et al. 2017 PMID 28536827). Disease-associated variants in the ACMG list of secondary findings genes are identified in approximately 3.4% of individuals (Johnston et al. 2022, PMID 34906458). This test is only validated for inherited gene alterations associated with the specified phenotype(s).
• Analytical Sensitivity: Sequencing: >94% for single nucleotide and >76% for small insertion/deletion variants for the nucleotides evaluated. Exonic deletions/duplications: >97% for unique regions of the genome. mtDNA: >97% for single nucleotide variants and 75% for large deletions. The lower limit of detection for mtDNA SNV variants is 5% and for mtDNA large deletions is 10%. This test is not validated to identify small deletions/insertions of greater than 20bp, exonic deletions and duplications in pseudogenes or other repetitive regions of the genome (e.g. segmental duplications), nucleotide repeat expansions, mitochondrial copy number or mosaicism. Disease-associated variants in regions that are not captured and/or sufficiently sequenced will not be detected by this assay.
• ACMG Secondary Findings Genes (v3.2): ACTA2, ACTC1, ACVRL1, APC, APOB, ATP7B, BAG3, BMPR1A, BRCA1, BRCA2, BTD, CACNA1S, CALM1, CALM2, CALM3, CASQ2, COL3A1, DES, DSC2, DSG2, DSP, ENG, FBN1, FLNC, GAA, GLA, HFE, HNF1A, KCNH2, KCNQ1, LDLR, LMNA, MAX, MEN1, MLH1, MSH2, MSH6, MUTYH, MYBPC3, MYH11, MYH7, MYL2, MYL3, NF2, OTC, PALB2, PCSK9, PKP2, PMS2, PRKAG2, PTEN, RB1, RBM20, RET, RPE65, RYR1, RYR2, SCN5A, SDHAF2, SDHB, SDHC, SDHD, SMAD3, SMAD4, STK11, TGFBR1, TGFBR2, TMEM127, TMEM43, TNNC1, TNNI3, TNNT2, TP53, TPM1, TRDN, TSC1, TSC2, TTN (A-band truncating variants only), TTR, VHL, WT1

Price: $7850.00
CPT Code: 81415, 81416

Test Information

• Test Method: DNA extraction (if applicable) and ultrasonic fragmentation; targeted capture of the coding regions and intron/exon boundaries of protein coding RefSeq genes using a TWIST custom exome library capture; next generation sequencing (NGS) on an Illumina NovaSeq instrument; alignment to the human reference genome (GRCh37/hg19) using the BurrowsWheeler Aligner (bwa); variant calling using GATK and detection of exonic deletions and duplications using ExomeDepth; mtDNA variant calling using GATK Mutect2 mitomode and detection of mtDNA deletions using eKLIPse; Sanger sequencing to confirm low quality and/or complex indel variants related to the specified phenotype(s); Review of sequence and dosage data for the specified genes by multiple staff members; Variant classification following ACMG criteria (if applicable). Bioinformatic analysis was performed using DDL pipeline DDL.TWISTExome.v1.2020_12_22, DDL.TWIST.Exome.Dosage.v1.2020_12_20 and DDL.TWISTExome.mtDNA.v1.2021_09_02.
• Clinical Sensitivity: The clinical sensitivity of this assay is dependent on the phenotypic information provided to the laboratory. A causative genetic variant is identified in approximately 20-30% of affected individuals (Farwell et al., 2015, PMID 25356970; Retterer et al., 2016, PMID 26633542; Yang et al., 2013, PMID 24088041). A causative genetic variant in mtDNA is identified in approximately 50-75% of adults and 10-20% of children diagnosed with a primary mitochondrial disorder (Zeviani et al. 2004 PMID 15358637, Schaefer et al. 2008 PMID 17886296, Koenig 2008 PMID 18410845, Poulton et al. 2017 PMID 28536827). Disease-associated variants in the ACMG list of secondary findings genes are identified in approximately 3.4% of individuals (Johnston et al. 2022, PMID 34906458). This test is only validated for inherited gene alterations associated with the specified phenotype(s).
• Analytical Sensitivity: Sequencing: >94% for single nucleotide and >76% for small insertion/deletion variants for the nucleotides evaluated. Exonic deletions/duplications: >97% for unique regions of the genome. mtDNA: >97% for single nucleotide variants and 75% for large deletions. The lower limit of detection for mtDNA SNV variants is 5% and for mtDNA large deletions is 10%. This test is not validated to identify small deletions/insertions of greater than 20bp, exonic deletions and duplications in pseudogenes or other repetitive regions of the genome (e.g. segmental duplications), nucleotide repeat expansions, mitochondrial copy number or mosaicism. Disease-associated variants in regions that are not captured and/or sufficiently sequenced will not be detected by this assay.
• ACMG Secondary Findings Genes (v3.2): ACTA2, ACTC1, ACVRL1, APC, APOB, ATP7B, BAG3, BMPR1A, BRCA1, BRCA2, BTD, CACNA1S, CALM1, CALM2, CALM3, CASQ2, COL3A1, DES, DSC2, DSG2, DSP, ENG, FBN1, FLNC, GAA, GLA, HFE, HNF1A, KCNH2, KCNQ1, LDLR, LMNA, MAX, MEN1, MLH1, MSH2, MSH6, MUTYH, MYBPC3, MYH11, MYH7, MYL2, MYL3, NF2, OTC, PALB2, PCSK9, PKP2, PMS2, PRKAG2, PTEN, RB1, RBM20, RET, RPE65, RYR1, RYR2, SCN5A, SDHAF2, SDHB, SDHC, SDHD, SMAD3, SMAD4, STK11, TGFBR1, TGFBR2, TMEM127, TMEM43, TNNC1, TNNI3, TNNT2, TP53, TPM1, TRDN, TSC1, TSC2, TTN (A-band truncating variants only), TTR, VHL, WT1

Target testing of one or more variants within the same patient.

Price: $400.00

CPT Code: 81403

Turnaround Time: 3 weeks

Platform: Sanger

Please provide report listing targeted variant information. If this individual was, or is part of a family, previously tested by the DNA Diagnostic Lab, please include the genetic ID. A positive control sample from a known carrier of the variant is required.

Targeted prenatal testing of one or more variants and maternal cell contamination study.

Price: $1350.00

CPT Code: 81479, 81265

Turnaround Time: 3 weeks

Platform: Sanger

Acceptable Sample Types (see Sample Requirements for details)

• Direct Villi (10mg, cleaned)
• Cultured Villi (2 T25 flasks)
• Cultured Amniocytes (2 T25 flasks)
• Extracted DNA (extracted from a CLIA-certified lab)
• Cord Blood

Please provide report listing targeted variant information. If this individual was, or is part of a family previously tested by the DNA Diagnostic Lab, please include the genetic ID. A maternal sample and a positive control sample from a known carrier of the variant are required.

Used to rule out maternal cell contamination of a fetal sample.

Price: $600.00

CPT Code: 81265

Turnaround Time: 1 week

Platform: Fragment Analysis

Acceptable Sample Types (see Sample Requirements for details)

• Direct Villi (10mg, cleaned)
• Cultured Villi (2 T25 flasks)
• Cultured Amniocytes (2 T25 flasks)
• Extracted DNA (extracted from a CLIA-certified lab)
• Cord Blood

If this individual was, or is part of a family, previously tested by the DNA Diagnostic Lab, please include the genetic ID. A maternal sample is required.