Test Id : MCP2Z

For skin biopsy or cultured fibroblast specimens, fibroblast culture testing will be performed at an additional charge. If viable cells are not obtained, the client will be notified.

Targeted testing (also called site-specific or known variant testing) is available for variants identified in this gene. See FMTT / Familial Variant, Targeted Testing, Varies. To obtain more information about this testing option, call 800-533-1710.

If the reason for testing indicates the RET gene or multiple endocrine neoplasia type 2 syndrome (MEN2), order RETZZ / Multiple Endocrine Neoplasia Type 2 Syndrome, RET, Full Gene Analysis, Varies. If this test is ordered in this situation, it will be canceled and RETZZ ordered and performed as the appropriate test.

Specimen preferred to arrive within 96 hours of collection.

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

Submit only 1 of the following specimens:

Specimen Type: Whole blood

Container/Tube:

Preferred: 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

Specimen Type: Skin biopsy

Supplies: Fibroblast Biopsy Transport Media (T115)

Container/Tube: Sterile container with any standard cell culture media (eg, minimal essential media, RPMI 1640). The solution should be supplemented with 1% penicillin and streptomycin.

Specimen Volume: 4-mm punch

Specimen Stability Information: Refrigerated (preferred)/Ambient

Additional Information: A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.

Specimen Type: Cultured fibroblast

Container/Tube: T-25 flask

Specimen Volume: 2 flasks

Collection Instructions: Submit confluent cultured fibroblast cells from a skin biopsy from another laboratory. Cultured cells from a prenatal specimen will not be accepted.

Specimen Stability Information: Ambient (preferred)/Refrigerated (<24 hours)

Additional Information: A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.

Specimen Type: Blood spot

Supplies: Card-Blood Spot Collection (Filtration Paper) (T493)

Container/Tube:

Preferred: Collection card (Whatman Protein Saver 903 Paper)

Acceptable: PerkinElmer 226 (formerly Ahlstrom 226) filter paper or blood spot collection card

Specimen Volume: 5 Blood spots

Collection Instructions:

1. An alternative blood collection option for a patient older than 1 year is a fingerstick. For detailed instructions, see How to Collect Dried Blood Spot Samples.

2. Let blood dry on the filter paper at ambient temperature in a horizontal position for a minimum of 3 hours.

3. Do not expose specimen to heat or direct sunlight.

4. Do not stack wet specimens.

5. Keep specimen dry.

Specimen Stability Information: Ambient (preferred)/Refrigerated

Additional Information:

1. Due to lower concentration of DNA yielded from blood spot, it is possible that additional specimen may be required to complete testing.

2. For collection instructions, see Blood Spot Collection Instructions

3. For collection instructions in Spanish, see Blood Spot Collection Card-Spanish Instructions (T777)

4. For collection instructions in Chinese, see Blood Spot Collection Card-Chinese Instructions (T800)

Specimen Type: Saliva

Patient Preparation: Patient should not eat, drink, smoke, or chew gum 30 minutes prior to collection.

Supplies: Saliva Swab Collection Kit (T786)

Specimen Volume: 1 Swab

Collection Instructions: Collect and send specimen per kit instructions.

Specimen Stability Information: Ambient 30 days

Additional Information: Due to lower concentration of DNA yielded from saliva, it is possible that additional specimen may be required to complete testing.

• Informed Consent for Genetic Testing
• Molecular Genetics: Neurology Patient Information
• Informed Consent for Genetic Testing (Spanish)

1. New York Clients-Informed consent is required. Please 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.

Blood: 1 mL; Skin biopsy, cultured fibroblasts, dried blood spots, or saliva: See Specimen Required

Establishing a molecular diagnosis in individuals with features of Rett syndrome and MECP2-related disorders

Identifying pathogenic variants within the MECP2 gene known to be associated with Rett syndrome and MECP2-related disorders, allowing for predictive testing of at-risk family members

This test utilizes next-generation sequencing to detect single nucleotide and copy number variants in the MECP2 gene associated with Rett syndrome and other MECP2-related disorders. See Method Description for additional details.

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

For skin biopsy or cultured fibroblast specimens, fibroblast culture testing will be performed at an additional charge. If viable cells are not obtained, the client will be notified.

Methyl-CpG-binding protein 2 (MeCP2) is encoded by the MECP2 gene located on the X chromosome and plays an important role in gene regulation. MeCP2 binds methylated DNA and is involved in both transcription activation and repression of other gene targets. As MECP2-related disorders are X-linked, female and male patients with disease-causing variants in the MECP2 gene present with unique variable phenotypes. In female patients, disease-causing variants in MECP2 can be associated with classic Rett syndrome, variant or atypical Rett syndrome, or mild learning disabilities. Distinct phenotypes in male patients with disease-causing MECP2 variants include MECP2-duplication syndrome; MECP2-related severe neonatal encephalopathy; pyramidal signs, parkinsonism, and macroorchidism syndrome (PPM-X); and syndromic/non-syndromic intellectual disability. MECP2 analysis is useful in identifying germline variants in individuals with these clinical presentations.

Rett Syndrome:

Classic Rett syndrome and other variant MECP2-related disorders result from loss of MeCP2 expression. Rett syndrome is an X-linked, panethnic condition associated with neurologic regression after a 6- to 18-month period of initial normal development. Main clinical findings include stereotypic hand movements such as hand wringing and loss of purposeful hand movements, loss of acquired language, and gait abnormalities. Bruxism, irregular breathing, seizures, acquired microcephaly, and impaired sleep patterns are also common.

Greater than 99% of individuals with Rett syndrome are simplex cases due to a de novo variant or inheritance from a parent with germline mosaicism. Asymptomatic or very mildly affected carrier mothers of classically affected daughters have been reported due to nonrandom X chromosome inactivation.

MECP2 Duplication Syndrome:

MECP2 duplication syndrome involves variably sized duplications of the MECP2 gene (ranging in size from 0.3 to 4 Mb) that result in MeCP2 protein overexpression. It is characterized by severe intellectual disability, hypotonia, feeding difficulties, and progressive spasticity. Seizures and recurrent respiratory infections are commonly reported as well.

In contrast to Rett syndrome, most male patients with MECP2 duplication syndrome inherit the duplication from their asymptomatic mothers, although rare de novo variants may occur. Additionally, female patients with an MECP2 duplication that do not demonstrate skewed X-inactivation may present with variable features of MECP2-duplication syndrome.

An interpretive report will be provided.

All detected variants are evaluated according to American College of Medical Genetics and Genomics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Clinical Correlations:

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

If testing was performed because of a clinically significant family history, it is often useful to first test an affected family member. Detection of a reportable variant in an affected family member would allow for more informative testing of at-risk individuals.

To discuss the availability of additional testing options or for assistance in the interpretation of these results, contact Mayo Clinic Laboratories' genetic counselors at 800-533-1710.

Technical Limitations:

Next-generation sequencing may not detect all types of genomic variants. In rare cases, false-negative or false-positive results may occur. The depth of coverage may be variable for some target regions; assay performance below the minimum acceptable criteria or for failed regions will be noted. Given these limitations, negative results do not rule out the diagnosis of a genetic disorder. If a specific clinical disorder is suspected, evaluation by alternative methods can be considered.

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 content, and repetitive sequences. Confirmation of select reportable variants will be performed by alternate methodologies based on internal laboratory criteria.

This test is validated to detect 95% of deletions up to 75 base pairs (bp) and insertions up to 47 bp. Deletions-insertions (delins) of 40 or more bp, including mobile element insertions, may be less reliably detected than smaller delins.

Deletion/Duplication Analysis:

This analysis targets single and multi-exon deletions/duplications; however, in some instances single exon resolution cannot be achieved due to isolated reduction in sequence coverage or inherent genomic complexity. Balanced structural rearrangements (such as translocations and inversions) may not be detected.

This test is not designed to detect low levels of mosaicism or to differentiate between somatic and germline variants. If there is a possibility that any detected variant is somatic, additional testing may be necessary to clarify the significance of results.

For detailed information regarding gene specific performance and technical limitations, see Method Description or contact a laboratory genetic counselor.

If the patient has had an allogeneic hematopoietic stem cell transplant or a recent heterologous blood transfusion, results may be inaccurate due to the presence of donor DNA. Call Mayo Clinic Laboratories for instructions for testing patients who have received a bone marrow transplant.

Reclassification of Variants:

At this time, it is not standard practice for the laboratory to systematically review previously classified variants on a regular basis. The laboratory encourages health care providers to contact the laboratory at any time to learn how the classification of a particular variant may have changed over time. Due to broadening genetic knowledge, it is possible that the laboratory may discover new information of relevance to the patient. Should that occur, the laboratory may issue an amended report.

Variant Evaluation:

Evaluation and categorization of variants is performed using published American College of Medical Genetics and Genomics and the Association for Molecular Pathology recommendations as a guideline.(1) Other gene-specific guidelines may also be considered. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. Variants classified as benign or likely benign are not reported.

Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and periodic updates to these tools may cause predictions to change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgement.

1. Richards S, Aziz N, Bale S, et al: 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. Genet Med. 2015 May;17(5):405-424

2. Sandweiss AJ, Brandt VL, Zoghbi HY: Advances in understanding of Rett syndrome and MECP2 duplication syndrome: prospects for future therapies. Lancet Neurol. 2020 Aug;19(8):689-698

3. Neul JL, Kaufmann WE, Glaze DG, et al: Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010 Dec; 68(6):944-950

Next generation sequencing (NGS) and/or Sanger sequencing is performed to test for the presence of variants in coding regions and intron/exon boundaries of the MECP2 gene, 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-based quantitative method is performed to test for the presence of deletions and duplications in the MECP2 gene.(Unpublished Mayo method)

The reference transcripts for the MECP2 gene are NM_004992.3 and NM_001110792.2. Reference transcript numbers may be updated due to transcript re-versioning. Always refer to the final patient report for gene transcript information referenced at the time of testing. Confirmation of select reportable variants may be performed by alternate methodologies based on internal laboratory criteria.

Varies

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• Prospective clients should contact their account representative. For assistance, contact Customer Service.

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.

81302

88233-Tissue culture, skin, solid tissue biopsy (if appropriate)

88240-Cryopreservation (if appropriate)