PMC Comprehensive Neuromuscular Disorders Panel

Associated Conditions
- Central Core Disease
- Centronuclear Myopathy
- Congenital Fiber Type Disproportion
- Congenital Muscular Dystrophy
- Congenital Myasthenic Syndrome
- Congenital Myopathy
- Dystroglycanopathies
- Dystrophinopathies
- Emery-Dreifuss Muscular Dystrophy
- Glycogen Storage Disease
- Limb-Girdle Muscular Dystrophy
- Mitochondrial DNA Depletion Syndrome
- Multiminicore Disease
- Multiple Acyl-CoA Dehydrogenase Deficiency
- Myofibrillar Myopathy
- Myotonia and Paramyotonia Congenita
- Nemaline Myopathy
- Primary carnitine deficiency
- Primary Coenzyme Q10 Deficiency
- Rhabdomyolysis
- Type VI Collagenopathies

Methodology

Targeted Exome/ Slice Exome (Next Generation Sequencing including Copy Number Variation)

Coverage

120x

Assay Information
- CAPN3: Deletion/duplication analysis is not offered for exon 24.
- CHRNE: Analysis includes the intronic variants NM_000080.3:c.-96C>T| NM_000080.3:c.-95G>A| and NM_000080.3:c.-94G>A.
- CTDP1: c.863+389C>T variant only.
- DDC: Deletion/duplication analysis is not offered for exons 10-11.
- DMD: Analysis guarantees del/dup detection at single-exon resolution.
- DOK7: Analysis includes the intronic variant NM_001301071.1:c.54+14_+28delGGGGGGGGGGGGCGC.
- FKTN: Analysis includes the intronic variant NM_001079802.1:c.647+2084G>T (also known as NM_001079802.1:c.648-1243G>T) and the ~3 kb retrotransposon insertion in the 3' UTR at position NM_001079802‚Äã.1:c.*4392_*4393.
- FLNC: Deletion/duplication analysis is not offered for exon 47. Sensitivity and specificity for single nucleotide variants| insertions and deletions in exons 47-48 may be reduced due to the presence of segmental duplications overlapping the region.
- GAA: Analysis includes the promoter variant NM_000152.3:c.-32-13T>G as well as the common exon 18 deletion.
- GFPT1: Sequencing analysis for exons 20 includes only cds +/- 10 bp.
- NEB: This assay detects the exon 55 deletion found in Ashkenazi Jewish individuals in association with nemaline myopathy. Exons 82-105 contain a large triplicated region. Deletion/duplication analysis excludes this region. Sequence changes in this region can be detected| but this assay cannot determine which of the three repeat units is affected (and zygosity is often ambiguous). All variants in this region are reported relative to the exon 82-89 repeat. Deletion/duplication analysis is not offered for exons 82-105. NEB variants in this region with no evidence towards pathogenicity are not included in this report| but are available upon request.
- PDSS1: Deletion/duplication analysis is not offered for exon 2.
- PGM1: Deletion/duplication analysis is not offered for exon 11.
- RAPSN: Analysis includes the promoter variants NM_005055.3:c.-210A>G and NM_005055.3:c.-199C>G.
- SDHA: Deletion/duplication analysis is not offered for this gene and sequencing analysis is not offered for exon 14. Sequencing analysis for exons 6-8 includes only cds +/- 10 bp.
- SELENON: Analysis includes the NM_20451.2:c.*1107T>C variant in the 3' UTR. Deletion/duplication analysis is not offered for exon 1.
- SMN1: Deletion/duplication analysis is not offered for exons 1-7 and sequencing analysis is not offered for this gene.; SMN1 or SMN2: The SMN1 gene is identical to the SMN2 gene with the exception of exon 8 (typically referred to as exon 7). This assay unambiguously detects SMN1 exon 8 copy number and sequence variants. Sequence variants outside of exon 8 will also be detected| but this assay cannot determine whether the variant is located in SMN1 or SMN2. SMN2 exon 8 copy number and the SMN2 exon 8 c.859G>C (p.Gly287Arg) modifier variant will be reported for individuals with a positive result in SMN1. CNVs of exons 1-7 of SMN1 or SMN2 (typically referred to as exons 1-6 in the literature) will not be reported. Variants in all exons with no evidence towards pathogenicity are not reported| but are available upon request. This assay cannot detect silent carriers (individuals that have 2 functional copies of SMN1 on one chromosome and zero copies on the other). Therefore a negative result for carrier testing greatly reduces but does not eliminate the chance that a person is a carrier. For individuals with 2 copies of SMN1| the residual risk of being a carrier has been reported to be 1 in 121 in African Americans| 1 in 345 in Ashkenazi Jewish individuals| 1 in 628 in Asians| 1 in 632 in Caucasians| and 1 in 1061 in Hispanic individuals (PMID: 23788250). The SMA-STAT test does not detect sequence variants in SMN1 or SMN2| and therefore cannot be used to identify compound heterozygotes.; SMN2: Deletion/duplication analysis is not offered for exons 1-7 and sequencing analysis is not offered for this gene.
- TPM3: Deletion/duplication analysis is not offered for exon 10.
- TSFM: Sequencing analysis is not offered for exon 5.
- TTN: Exons 45-46| 147| 149| 164| 172-201 (NM_001267550.2) are excluded from analysis. TTN variants are included in the primary report based on functional effect and/or location. A complete list of variants of uncertain significance| likely benign and benign variants in TTN is available upon request. Variants are named relative to the NM_001267550.2 (meta) transcript. Variants in the coding sequence and intronic boundaries of the clinically relevant NM_133378.4 (N2A) and fetal isoforms are reported (PMID: 25589632| 29598826| 29691892| 31660661)| with the exception of the PEVK tandem repeat region (172-198) (PMID: 28040389).

Ordering information

Turnaround Time: 10 business days

Preferred Speciment: Saliva Kits (available upon request)

Alternate Specimens: Nail clippings or 3-mL whole blood in purple top EDTA tube

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Limitations

All sequencing technologies have limitations. A negative result from this analysis does not rule out a possible genetic diagnosis as some variants may not be detected by this test. This test is not designed to detect low level mosaicism, structural rearrangements, indels >40bp, deep intronic variants of unknown clinical significance, or large cytogenetic CNVs. Certain inherent qualities of the human genome, for example repetitive regions/homopolymers, GC rich, pseudogenes, and rare polymorphisms, pose significant technical challenges such as sequence misalignment that may potentially impact the accuracy of the results. False negative results may also occur in the setting of allogeneic bone marrow, stem cell transplantation, active or chronic hematologic conditions, recent blood transfusions, suboptimal DNA quality or PCR trace contamination. Other potential sources of error include sample mix-ups and clerical issues.

References
- 1. Richards S et al. Genetics in medicine. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. 2015 May;17(5):405-24 (PMID: 25741868)
- 2. GnomAD (gnomAD)
- 3. CSPEC (ClinGen variant classification rules registry) Criteria Specification Registry
- 4. Normal copy number variation in healthy individuals database of genomic variants: http://dgv.tcag.ca/dgv/app/home
- 5. Riggs, E.R., Andersen, E.F., Cherry, A.M. et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med 22, 245–257 (2020). https://doi.org/10.1038/s41436-019-0686-8
- 6. Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, Maglott DR. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014 Jan 1;42(1):D980-5. doi: 10.1093/nar/gkt1113. PubMed PMID: 24234437.
- 7. Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), Copyright® 1966-2012. World Wide Web URL: http://omim.org.
- 8. http://tinyurl.com/ACMGv4 (ACMG/ Clingen draft Interpretation SOP); clingen_variant-curation_sopv1.pdf

Tagged Genes

Primary panel:

211 genes selected

ABHD5 ACAD9 ACADM ACADVL ACTA1 ADSSL1 AGK AGL AGRN AHCY ALDOA ALG14 ALG2 AMACR AMPD1 ANO5 ATP2A1 ATP7B B3GALNT2 B4GAT1 BAG3 BIN1 C1QBP CACNA1S CAPN3 CASQ1 CAV3 CCDC78 CFL2 CHAT CHKB CHRNA1 CHRNB1 CHRND CHRNE CLCN1 CNTN1 COL12A1 COL13A1 COL6A1 COL6A2 COL6A3 COLQ COQ2 COQ4 COQ7 COQ8A COQ9 COX15 COX20 COX6B1 CPT1A CPT2 CRYAB CTDP1 DAG1 DDC DES DGUOK DMD DNA2 DNAJB6 DNM2 DOK7 DPAGT1 DPM1 DPM2 DPM3 DYSF EMD ENO3 ETFA ETFB ETFDH FBXL4 FDX2 FHL1 FKBP14 FKRP FKTN FLAD1 FLNC GAA GATM GBE1 GFER GFPT1 GMPPB GNE GOSR2 GYG1 GYS1 HACD1 HADH HADHA HADHB HMBS HNRNPA2B1 HNRNPDL ISCU ISPD ITGA7 KBTBD13 KCNJ2 KLHL40 KLHL41 LAMA2 LAMP2 LARGE1 LDB3 LDHA LMNA LMOD3 LPIN1 MAN2B1 MAP3K20 MATR3 MEGF10 MGME1 MICU1 MPV17 MTM1 MUSK MYH2 MYH3 MYH7 MYL2 MYO18B MYOT MYPN NEB OPA1 OPA3 ORAI1 PDSS1 PDSS2 PFKM PGAM2 PGK1 PGM1 PHKA1 PHKB PLEC PNPLA2 PNPLA8 POGLUT1 POLG POLG2 POMGNT1 POMGNT2 POMK POMT1 POMT2 PREPL PUS1 PYGM PYROXD1 RAPSN RBCK1 RNASEH1 RRM2B RXYLT1 RYR1 SCN4A SDHA SELENON SGCA SGCB SGCD SGCG SIL1 SLC16A1 SLC18A3 SLC22A5 SLC25A20 SLC25A3 SLC25A4 SLC25A42 SLC5A7 SMCHD1 SMN1 SMN2 SMPX SPEG SQSTM1 STAC3 STIM1 SUCLA2 SUCLG1 SYT2 TANGO2 TAZ TCAP TIA1 TK2 TNNT1 TNPO3 TOR1AIP1 TPM2 TPM3 TRAPPC11 TRIM32 TRMT5 TSFM TTN TWNK TYMP VAMP1 VCP VMA21 YARS2

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Test Description

Associated Conditions

Methodology

Coverage

Assay Information

Ordering information

Limitations

References

Tagged Genes