Myotilinopathy via the MYOT Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
366 MYOT$680.00 81405 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity
Myotilinopathy is a rare disorder (see for example, Moore et al. J Neuropathol Exp Neurol. 65:995-1003, 2006).  Hauser et al. (Am J Hum Genet 71:1428–1432, 2002) screened 86 muscular dystrophy families, 44 of which demonstrated autosomal dominant inheritance, and found one with a causative MYOT mutation.  The relative frequencies of mutations found in the Mayo Clinic MFM cohort was LDB3 (14%), MYOT (13%), DES (8%), FLNC (4%), BAG3 (4%), and CRYAB (3%) (Selcen and Engel, GeneReviews 2010).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 MYOT$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Features
Mutations in the myotilin gene (MYOT), also referred to as titin immunoglobulin domain protein gene (TTID), cause limb girdle muscular dystrophy type 1A (LGMD1A; OMIM 159000; Hauser et al. Hum Mol Genet 9:2141-2147, 2000) and myofibrillar myopathy (OMIM 609200; Selcen and Engel. Neurology 62:1363-1371, 2004). Patients with the LGMD phenotype exhibit distal weakness with mean age at onset of 27 years. Proximal weakness develops later in life, and approximately half of all patients exhibit a distinct nasal, dysarthric pattern of speech (Hauser at al. Amer J Hum Genet 71:1428-1432, 2002). CK levels are generally elevated 1.6 to 9 fold above normal range (Hauser et al. 2002). Myotilin-related MFM exhibits later onset (50 - 77 years) and has features of peripheral neuropathy with hyporeflexia, cardiomyopathy, and distal weakness greater than proximal weakness (Selcen and Engel, 2004). Stained with trichome, abnormal muscle fibers are seen containing hyaline structures and vacuoles containing membrane fragments from disintegrated sarcomeric Z disc and myofibrils (Selcen et al. Brain 127:439-451, 2004). With electron microscopy, affected muscle fibers reveal progressive degeneration of myofibrils beginning at the Z-disk. Immunohistochemical staining of the structurally abnormal fibers reveals abnormal expression and accumulation of several proteins, including myotilin, desmin, alpha-B crystalline, dystrophin and β-amyloid precursor protein (Selcen et al. 2004). Based upon studies of small cohorts, LGMD1A patients developed hyporeflexia later in the disease than myotilin-related MFM patients, thus tentatively differentiating these allelic disorders.
Myotilinopathy is inherited in an autosomal dominant manner. The MYOT gene (OMIM 604103) encodes myotilin, a sarcomeric protein that binds actin either alone or in conjunction with alpha-actinin, an actin crosslinking protein. Thus, myotilin plays a key role in stabilization and anchorage of thin filaments, which may be a prerequisite for correct Z disc organization (Salmikangas et al. Hum Mol Genet 12:189-203, 2003). Nearly all MYOT mutations thus far reported result in amino acid substitutions in the serine rich exon 2. One missense mutation in exon 9 has been reported to be causative for LGMD1A (Shalby et al. J Neuropath Exp Neurol 68:701-707, 2009). Other genes involved with MFM include DES, FLNC, LDB3, CRYAB, and BAG3.
Testing Strategy
Myotilin is coded by exons 2-10 of the MYOT gene located on chromosome 5q31. Testing is accomplished by amplifying each coding exon and ~20 bp of adjacent noncoding sequence, then determining the nucleotide sequence using standard dideoxy sequencing methods and a capillary electrophoresis instrument. We will also sequence any single exon (Test #100) in family members of patients with a known mutation or to confirm research results.
Indications for Test
Individuals with symptoms consistent with LGMD or myofibrillar myopathy and autosomal dominant inheritance. Symptomatic individuals with muscle biopsies demonstrating centrally located nuclei and fiber size variation.


Official Gene Symbol OMIM ID
MYOT 604103
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Genetic Counselors
  • Duygu Selcen, Andrew G Engel (2010). "Myofibrillar Myopathy."
  • Hauser, M. A., (2000). "Myotilin is mutated in limb girdle muscular dystrophy 1A." Hum Mol Genet 9(14): 2141-7. PubMed ID: 10958653
  • Hauser, M. A., (2002). "myotilin Mutation found in second pedigree with LGMD1A." Am J Hum Genet 71(6): 1428-32. PubMed ID: 12428213
  • Moore A. 2006. RPGR is mutated in patients with a complex X linked phenotype combining primary ciliary dyskinesia and retinitis pigmentosa. Journal of Medical Genetics 43: 326-333. PubMed ID: 16055928
  • Salmikangas, P., (2003). "Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly." Hum Mol Genet 12(2): 189-203. PubMed ID: 12499399
  • Selcen D, Ohno K, Engel AG. 2004. Myofibrillar myopathy: clinical, morphological and genetic studies in 63 patients. Brain 127(Pt 2): 439-451. PubMed ID: 14711882
  • Selcen, D., Engel, A. G. (2004). "Mutations in myotilin cause myofibrillar myopathy." Neurology 62(8): 1363-71. PubMed ID: 15111675
  • Shalaby, S., (2009). "Defective myotilin homodimerization caused by a novel mutation in MYOT exon 9 in the first Japanese limb girdle muscular dystrophy 1A patient." J Neuropathol Exp Neurol 68(6): 701-7. PubMed ID: 19458539
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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Ordering Options

myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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