X-linked Myotubular Myopathy: MTM1 Gene Sequencing

Condition Description

X-linkedmyotubular myopathy (XLMTM) is a non-progressive muscle disease associated withhypotonia, respiratory distress, and delayed motor milestones. Four forms ofthe disease have been described.

  • Severe (classic) XLMTM presents prenatally with polyhydramnios and decreased fetal movement and in newborns with hypotonia and respiratory distress. Affected males have chronic ventilator dependence and grossly delayed motor milestones; they often fail to walk. Infants with severe XLMTM often have typical myopathic facies with dolicocephaly, high forehead, long face with midface hypoplasia, and narrow high-arched palate with subsequent severe malocclusion. Additional features can include length greater than the 90th centile with a proportionately lower weight, long fingers and/toes, cryptorchidism, contractures including clubfeet, areflexia, ptosis, severe myopia, dental malocclusion, and scoliosis. In the absence of significant hypoxic episodes, cognitive development is normal in the majority of individuals. Death in infancy is common.
  • Males with moderate XLMTM achieve motor milestones more quickly than males with the severe form; about 40% require no ventilator support or intermittent support. Males with moderate or even mild disease are at increased risk for respiratory decompensation with intercurrent illness and may require transient or increased ventilatory support. They are also at risk for some of the same medical complications as those with severe XLMTM.
  • Males with mild XLMTM may require ventilatory support only in the newborn period; they have minimally delayed motor milestones, are able to walk, and lack myopathic facies.
  • Adult-onset XLMTM is very rare; affected males do not have clinical manifestations in infancy but develop slowly progressive myopathy in adulthood. They may require respiratory support at night.

Themuscle disease of XLMTM is not progressive; muscle strength improves slowlyover time. Phenotype can vary within a family. Female carriers of XLMTM aregenerally asymptomatic, although rare manifesting heterozygotes have beendescribed, usually due to skewed X-inactivation.

Thediagnosis of XLMTM has traditionally relied upon identification ofcharacteristic histopathologic changes in muscle samples from males withneonatal hypotonia and a family history consistent with X-linked inheritance.These histopathologic changes, however, are not found in all affectedindividuals, and are not specific to XLMTM. An abnormal muscle biopsy is foundin only 50%-70% of obligate carrier females; thus, muscle biopsy studies arenot sensitive enough for carrier testing.

MTM1 (Xq28) is the only gene associatedwith XLMTM; its protein product, myotubularin, is required for muscle celldifferentiation. Molecular genetic testing of MTM1 detects mutations in60%-98% of affected individuals; in individuals with mild XLMTM, fewer than 20%of mutations are identified. Approximately 7% of mutations are large deletionsof one or more exons of MTM1. In simplex cases (i.e., a singleoccurrence in a family), there is a probability of 80%-90% that a woman is acarrier if her son has a confirmed MTM1 mutation. Thus, about 10%-20% ofmales who represent simplex cases have a de novo disease-causingmutation in MTM1 and a mother who is not a carrier. Germline mosaicismhas been reported.

For patients with suspected XLMTM, sequence analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by full gene sequencing, deletion/duplication analysis is appropriate.

Click here for the GeneTests summary on this condition.

Genes (1)


This test is indicated for:

  • Confirmation of a clinical/biochemical diagnosis of XLMTM
  • Carrier testing in adult females with a family history of XLMTM


PCR amplification of 14 exons contained in the MTM1 gene is performed on the patient's genomic DNA. Direct sequencing of amplification products is performed in both forward and reverse directions, using automated fluorescence dideoxy sequencing methods. The patient's gene sequences are then compared to a normal reference sequence. Sequence variations are classified as mutations, benign variants unrelated to disease, or variations of unknown clinical significance. Variants of unknown clinical significance may require further studies of the patient and/or family members. This assay does not interrogate the promoter region, deep intronic regions, or other regulatory elements, and does not detect large deletions.


Clinical Sensitivity: Molecular genetic testing of MTM1 detects mutations in 60%-98% of affected individuals; in individuals with mild XLMTM, fewer than 20% of mutations are identified. Mutations in the promoter region, some mutations in the introns and other regulatory element mutations cannot be detected by this analysis. Large deletions will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient's biochemical phenotype.

Analytical Sensitivity: ~99%

Specimen Requirements

Listed below are EGL's preferred sample criteria. For any questions, please call 470.378.2200 and ask to speak with a laboratory genetic counselor (eglgc@egl-eurofins.com).
Submit only 1 of the following specimen types
DNA, Isolated

Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Collection and Shipping
Refrigerate until time of shipment in 100 ng/µL in TE buffer. Ship sample at room temperature with overnight delivery.
Whole Blood (EDTA)

EDTA (Purple Top)
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
Collection and Shipping
Ship sample at room temperature for receipt at EGL within 72 hours of collection. Do not freeze.

Oragene™ Saliva Collection Kit
Orangene™ Saliva Collection Kit used according to manufacturer instructions. Please contact EGL for a Saliva Collection Kit for patients that cannot provide a blood sample.
Collection and Shipping
Please do not refrigerate or freeze saliva sample. Please store and ship at room temperature.

Special Instructions

Submit copies of diagnostic biochemical test results with the sample, if appropriate. Contact the laboratory if further information is needed.

Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of EGL Genetics, please submit a copy of the sequencing report with the test requisition.

  • Deletion/duplication analysis of the MTM1 gene by CGH array is available for those individuals in whom sequence analysis is negative (ZA).
  • A CGH array-based test for deletion/duplication analysis of 64 different X-linked intellectual disability genes is available (OL).
  • Custom diagnostic mutation analysis (KM) is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.
  • Prenatal testing is available to adult females who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.

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