Order Code MNDP Inherited Motor Neuron Disease Gene Panel, Varies

Ordering Guidance

First tier testing for a diagnosis of dementia or amyotrophic lateral sclerosis is C9ORF / C9orf72 Hexanucleotide Repeat, Molecular Analysis, Varies, which is included with this test but is also available separately.

For individuals with both ALS and evidence of dementia, consider AFTDP / Inherited Frontotemporal Dementia and Amyotrophic Lateral Sclerosis Gene Panel, Varies,

Targeted testing for familial variants (also called site-specific or known variants testing) is available for the genes on this panel. See FMTT / Familial Variant, Targeted Testing, Varies. To obtain more information about this testing option, call 800-533-1710.

Customization of this panel and single gene analysis for any gene present on this panel are available. For more information see CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies.

Shipping Instructions

Specimen preferred to arrive within 96 hours of collection.

Specimen Required

Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing.Â For instructions for testing patients who have received a bone marrow transplant, call 800-533-1710.

Specimen Type: Whole blood

Container/Tube: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send whole blood specimen in original tube. Do not aliquot.

Specimen Stability Information: Ambient (preferred)/Refrigerated

Additional Information: To ensure minimum volume and concentration of DNA is met, the preferred volume of blood must be submitted. Testing may be canceled if DNA requirements are inadequate.

Forms

1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file.

The following documents are available:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing (Spanish) (T826)

2. Molecular Genetics: Neurology Patient Information

3. If not ordering electronically, complete, print, and send a Neurology Specialty Testing Client Test Request (T732) with the specimen.

Useful For

Establishing a molecular diagnosis for patients with motor neuron disease

Identifying variants within genes known to be associated with motor neuron disease, allowing for predictive testing of at-risk family members

Genetics Test Information

This test utilizes next-generation sequencing to detect single nucleotide and copy number variants in 34 genes associated with motor neuron disease: ALS2, ANG, ANXA11, ASAH1, CCNF, CHCHD10, CHMP2B, DCTN1, ERBB4, FIG4, FUS, HEXB, HNRNPA1, HNRNPA2B1, KIF5A, MATR3, NEFH, OPTN, PFN1, SETX, SIGMAR1, SOD1, SPG11, SPTLC1, SQSTM1, TAF15, TARDBP, TBK1, TIA1, TUBA4A, UBQLN2, VAPB, VCP, VRK1. A polymerase chain reaction-based assay is utilized to detect C9orf72 GGGGCC hexanucleotide repeat expansions. See Targeted Genes and Methodology Details for Inherited Motor Neuron Disease Gene Panel and Method Description for additional details.

Identification of a disease-causing variant may assist with diagnosis, prognosis, clinical management, recurrence risk assessment, familial screening, and genetic counseling for motor neuron disease.

Special Instructions

Method Name

Sequence Capture and Targeted Next-Generation Sequencing followed by Polymerase Chain Reaction (PCR) and Sanger Sequencing

Reporting Name

Motor Neuron Disease Gene Panel

Specimen Type

Varies

Specimen Minimum Volume

1 mL

Specimen Stability Information

Specimen Type	Temperature	Time	Special Container
Varies	Varies

Reject Due To

All specimens will be evaluated at Mayo Clinic Laboratories for test suitability.

Reference Values

An interpretive report will be provided.

C9orf72 Repeats:

Normal alleles (reference):<20 GGGGCC repeats

Indeterminate alleles: 20-100 GGGGCC repeats

Pathogenic alleles:* >100 GGGGCC repeats

*The exact cutoff for pathogenicity is currently undefined. Although additional studies are needed to confirm if the cutoff for pathogenicity is 100 repeats, most individuals affected with a C9orf72-related disorder have C9orf72 hexanucleotide repeat expansions with hundreds to thousands of repeats.

Method Description

Next-generation sequencing (NGS) and/or Sanger sequencing are performed to test for the presence of variants in coding regions and intron/exon boundaries of the genes analyzed, as well as some other regions that have known disease-causing variants. The human genome reference GRCh37/hg19 build was used for sequence read alignment. At least 99% of the bases are covered at a read depth over 30X. Sensitivity is estimated at above 99% for single nucleotide variants, above 94% for deletion-insertions (delins) less than 40 base pairs (bp), above 95% for deletions up to 75 bp and insertions up to 47 bp. NGS and/or a polymerase chain reaction (PCR)-based quantitative method is performed to test for the presence of deletions and duplications in the genes analyzed.

There may be regions of genes that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences. See Targeted Genes and Methodology Details for Inherited Motor Neuron Disease Gene Panel for details regarding the targeted genes analyzed for each test and specific gene regions not routinely covered.(Unpublished Mayo method)

Confirmation of select reportable variants may be performed by alternate methodologies based on internal laboratory criteria.

A combined amplicon-length and repeat-primed PCR-based assay is utilized to size alleles up to approximately 145 repeats and detect expansions of GGGGCC hexanucleotide repeat region in the C9orf72 gene.(Ida CM, Lundquist PA, Bram E, et al: Evaluation of single-tube combined amplicon-length and repeat-primed long-read PCR assay for clinical detection and characterization of C9orf72 hexanucleotide repeat expansion. Abstract 731. 2017 ACMG Annual Clinical Genetics Meeting. Phoenix, AZ. March 23, 2017)

Genes analyzed: ALS2, ANG, ANXA11, ASAH1, CCNF, CHCHD10, CHMP2B, DCTN1, ERBB4, FIG4, FUS, HEXB, HNRNPA1, HNRNPA2B1, KIF5A, MATR3, NEFH, OPTN, PFN1, SETX, SIGMAR1, SOD1, SPG11, SPTLC1, SQSTM1, TAF15, TARDBP, TBK1, TIA1, TUBA4A, UBQLN2, VAPB, VCP, VRK1

Day(s) Performed