# X-Linked Myotubular Myopathy in a Female Patient with a Pathogenic Variant in the _Mtm1_ Gene
## 4 Discussion  
X-linked myotubular myopathy predominantly affects males and is generally characterized by early onset and severe phenotype, often leading to early death [8]. However, there are approximately 40 described cases of female patients with MTM. All of them had symptoms characteristic for congenital myopathy. Examination of muscle tissue biopsy showed signs of centronuclear myopathy [8]. All female patients were carriers of pathogenic variants in the _MTM1_ gene. Some of them were the only affected family members; others had male relatives who were affected. Most affected females had skewed X chromosome inactivation [8; 16], but in some cases, no skewed inactivation was detected [8; 17]. All of them were diagnosed with myotubular myopathy. With that, to establish the \"X-linked myotubular myopathy\" diagnosis in a female patient, it is not enough to detect a pathogenic variant in the _MTM1_ gene and skewed X chromosome inactivation without _MTM_ mRNA analysis and muscle tissue biopsy examination results. It is necessary to determine that the active chromosome carries the pathogenic variant in the _MTM1_ gene. The detected c.1261-10A>G nucleotide sequence variant was first described as pathogenic by [PERSON] in 1997. This variant was detected in four male patients with clinical and histological signs of centronuclear myopathy. The analysis of three patients' mRNA (extracted from peripheral blood lymphocytes) of the _MTM1_ gene detected a transcript of this gene with a nine-nucleotide elongation of exon 12, leading to an insertion of three amino acids Phe-Ile-Gln on the protein level [11]. In 1998, [PERSON] also described this variant in a Japanese male patient with clinical and histochemical signs of centronuclear myopathy. mRNA (extracted from muscle tissue) of the _MTM1_ gene was also analyzed for this patient [18]. In the following years, this variant was described as pathogenic multiple times [19; 20] and is currently considered to be a common pathogenic variant leading to severe CNM in male patients. The c.1261-10A>G variant is localized in intron 11 of the _MTM1_ gene. According to the data presented in literature, the Splice AI prediction program, and the mRNA analysis of the proband's _MTM1_ gene carried out in our laboratory, the detected variant leads to a disruption in the acceptor splice site of exon 12 and causes the activation of a cryptic site, which leads to a nine-nucleotide elongation of exon 12 [11] and, therefore, the insertion of three amino acids on the protein level. The insertion occurs in a highly conservative catalytic PTP domain of myotubularin, which presumably affects the catalytic activity of the protein. The c.1261-10A>G nucleotide sequence variant is not registered in the control cohorts of the Genome Aggregation Database (gnomAD), RuExac (the genetic variant database of the Research Centre for Medical Genetics accumulating data of 2090 patients) [21], and RuSeq (unified Russian genetic variant database from the Genetic laboratory, SerbaLab, and Saint-Petersburg's municipal hospital N 40 accumulating data of 1500 patients) [22]. According to the data presented in HGMD [5], there are 24 described pathogenic variants in the exon 12 _MTM1_ gene. Of these, 33.4% (8) are missense mutations, 20.8% (5) are deletions, 16.6% (4) are splice site mutations, 16.6% (4) are nonsense mutations, and 12.6% (3) are duplications. This corresponds with the general distribution of the _MTM1_ pathogenic variant. With that, most of the pathogenic variants (both in general for the gene and in exon 12) are missense mutations, which may correlate with the enzyme activity of the myotubularin protein. Out of the 93 described deletions and duplications in the _MTM1_ gene, 12 are pathogenic variants not leading to a frameshift. Thus, despite the fact that the c.1261-10A>G nucleotide sequence variant does not lead to a frameshift, it is pathogenic.