{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:43:24Z","timestamp":1760150604043,"version":"build-2065373602"},"reference-count":42,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,12,3]],"date-time":"2023-12-03T00:00:00Z","timestamp":1701561600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy resulting from dysfunction of the protein myotubularin encoded by the MTM1 gene. XLMTM has a high neonatal and infantile mortality rate due to a severe myopathic phenotype and respiratory failure. However, in a minority of XLMTM cases, patients present with milder phenotypes and achieve ambulation and adulthood. Notable facial dysmorphia is also present. Methods: We investigated the genotype\u2013phenotype correlations in newly diagnosed XLMTM patients in a patients\u2019 cohort (previously published data plus three novel variants, n = 414). Based on the facial gestalt difference between XLMTM patients and unaffected controls, we investigated the use of the Face2Gene application. Results: Significant associations between severe phenotype and truncating variants (p &lt; 0.001), frameshift variants (p &lt; 0.001), nonsense variants (p = 0.006), and in\/del variants (p = 0.036) were present. Missense variants were significantly associated with the mild and moderate phenotype (p &lt; 0.001). The Face2Gene application showed a significant difference between XLMTM patients and unaffected controls (p = 0.001). Conclusions: Using genotype\u2013phenotype correlations could predict the disease course in most XLMTM patients, but still with limitations. The Face2Gene application seems to be a practical, non-invasive diagnostic approach in XLMTM using the correct algorithm.<\/jats:p>","DOI":"10.3390\/genes14122174","type":"journal-article","created":{"date-parts":[[2023,12,4]],"date-time":"2023-12-04T03:40:58Z","timestamp":1701661258000},"page":"2174","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Prognostic Value of Genotype\u2013Phenotype Correlations in X-Linked Myotubular Myopathy and the Use of the Face2Gene Application as an Effective Non-Invasive Diagnostic Tool"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9076-313X","authenticated-orcid":false,"given":"Katar\u00edna","family":"Ku\u0161\u00edkov\u00e1","sequence":"first","affiliation":[{"name":"Department of Pediatric Neurology, Faculty of Medicine, Comenius University Bratislava and National Institute of Children\u2019s Diseases, 83340 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"\u0160olt\u00fdsov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, 84215 Bratislava, Slovakia"},{"name":"Institute for Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, 84505 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrej","family":"Ficek","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, 84215 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4215-8258","authenticated-orcid":false,"given":"Ren\u00e9 G.","family":"Feichtinger","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital, SalzburgerLandeskliniken (SALK), Paracelsus Medical University Salzburg, 5020 Salzburg, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6970-336X","authenticated-orcid":false,"given":"Johannes A.","family":"Mayr","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital, SalzburgerLandeskliniken (SALK), Paracelsus Medical University Salzburg, 5020 Salzburg, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7927-9777","authenticated-orcid":false,"given":"Martina","family":"\u0160kopkov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Metabolic Disorders, Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Science, 84505 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5725-6424","authenticated-orcid":false,"given":"Daniela","family":"Ga\u0161per\u00edkov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Metabolic Disorders, Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Science, 84505 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miriam","family":"Koln\u00edkov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Faculty of Medicine, Comenius University Bratislava and National Institute of Children\u2019s Diseases, 83340 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karoline","family":"Ornig","sequence":"additional","affiliation":[{"name":"Division of Neuropathology, Department of Pathology and Molecular Pathology, Neuromed Campus, Kepler University Hospital, Johannes Kepler University, 4020 Linz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ognian","family":"Kalev","sequence":"additional","affiliation":[{"name":"Division of Neuropathology, Department of Pathology and Molecular Pathology, Neuromed Campus, Kepler University Hospital, Johannes Kepler University, 4020 Linz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6750-2599","authenticated-orcid":false,"given":"Serge","family":"Weis","sequence":"additional","affiliation":[{"name":"Division of Neuropathology, Department of Pathology and Molecular Pathology, Neuromed Campus, Kepler University Hospital, Johannes Kepler University, 4020 Linz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denisa","family":"Weis","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Kepler University Hospital Med Campus IV, Johannes Kepler University, 4020 Linz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8910","DOI":"10.1073\/pnas.160255697","article-title":"Myotubularin, a protein tyrosine phosphatase mutated in myotubular myopathy, dephosphorylates the lipid second messenger, phosphatidylinositol 3-phosphate","volume":"97","author":"Taylor","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.tcb.2006.06.001","article-title":"Myotubularin phosphatases: Policing 3-phosphoinositides","volume":"16","author":"Robinson","year":"2006","journal-title":"Trends Cell Biol."},{"key":"ref_3","first-page":"1","article-title":"Myotubularin MTM1 Involved in Centronuclear Myopathy and its Roles in Human and Yeast Cells","volume":"8","author":"Bertazzi","year":"2015","journal-title":"J. Mol. Genet. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/sj.ejhg.5200189","article-title":"Genomic organization of the MTM1 gene implicated in X-linked myotubular myopathy","volume":"6","author":"Laporte","year":"1998","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1001\/archneur.1966.00470070005001","article-title":"Myotubular myopathy. Persistence of fetal muscle in an adolescent boy","volume":"14","author":"Spiro","year":"1966","journal-title":"Arch. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/S0168-9525(01)02245-4","article-title":"The myotubularin family: From genetic disease to phosphoinositide metabolism","volume":"17","author":"Laporte","year":"2001","journal-title":"Trends Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/S0022-3476(99)70417-8","article-title":"Medical complications in long-term survivors with X-linked myotubular myopathy","volume":"134","author":"Herman","year":"1999","journal-title":"J. Pediatr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/S0960-8966(02)00153-0","article-title":"Genotype-phenotype correlations in X-linked myotubular myopathy","volume":"12","author":"McEntagart","year":"2002","journal-title":"Neuromuscul. Disord."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/ejhg.2012.201","article-title":"Expanding the MTM1 mutational spectrum: Novel variants including the first multi-exonic duplication and development of a locus-specific database","volume":"21","author":"Oliveira","year":"2013","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_10","unstructured":"Adam, M.P., Ardinger, H.H., Pagon, R.A., and Wallace, S.E. (2023, November 01). X-Linked Myotubular Myopathy, GeneReviews\u00ae [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1432\/."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1016\/j.nmd.2021.08.003","article-title":"X-linked myotubular myopathy","volume":"31","author":"Lawlor","year":"2021","journal-title":"Neuromuscul. Disord."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/j.nmd.2013.06.008","article-title":"Fatal hepatic hemorrhage by peliosis hepatis in X-linked myotubular myopathy: A case report","volume":"23","author":"Motoki","year":"2013","journal-title":"Neuromuscul. Disord."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1212\/WNL.0000000000004415","article-title":"A natural history study of X-linked myotubular myopathy","volume":"89","author":"Amburgey","year":"2017","journal-title":"Neurology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1002\/mus.26018","article-title":"A multicenter, retrospective medical record review of X-linked myotubular myopathy: The recensus study","volume":"57","author":"Beggs","year":"2018","journal-title":"Muscle Nerve"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/s41591-018-0279-0","article-title":"Identifying facial phenotypes of genetic disorders using deep learning","volume":"25","author":"Gurovich","year":"2019","journal-title":"Nat. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1002\/(SICI)1098-1004(200005)15:5<393::AID-HUMU1>3.0.CO;2-R","article-title":"MTM1 mutations in X-linked myotubular myopathy","volume":"15","author":"Laporte","year":"2000","journal-title":"Hum. Mutat."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Bendl, J., Stourac, J., Salanda, O., Pavelka, A., Wieben, E.D., Zendulka, J., Brezovsky, J., and Damborsky, J. (2014). PredictSNP: Robust and accurate consensus classifier for prediction of disease-related mutations. PLoS Comput. Biol., 10.","DOI":"10.1371\/journal.pcbi.1003440"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"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","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e1852","DOI":"10.1212\/WNL.0000000000007319","article-title":"X-linked myotubular myopathy: A prospective international natural history study","volume":"92","author":"Annoussamy","year":"2019","journal-title":"Neurology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1007\/s00415-015-7757-9","article-title":"Centronuclear myopathies: Genotype-phenotype correlation and frequency of defined genetic forms in an Italian cohort","volume":"262","author":"Fattori","year":"2015","journal-title":"J. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1007\/s00401-017-1748-0","article-title":"Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: Delineating diagnostic clues","volume":"134","author":"Biancalana","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.nmd.2004.12.005","article-title":"Characterization of MTM1 mutations in 31 Japanese families with myotubular myopathy, including a patient carrying 240 kb deletion in Xq28 without male hypogenitalism","volume":"15","author":"Tsai","year":"2005","journal-title":"Neuromuscul. Disord."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/s00439-002-0869-1","article-title":"Characterisation of mutations in 77 patients with X-linked myotubular myopathy, including a family with a very mild phenotype","volume":"112","author":"Biancalana","year":"2003","journal-title":"Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1002\/humu.10033","article-title":"Characterization of mutations in fifty North American patients with X-linked myotubular myopathy","volume":"19","author":"Herman","year":"2002","journal-title":"Hum. Mutat."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1093\/hmg\/6.9.1505","article-title":"Mutations in the MTM1 gene implicated in X-linked myotubular myopathy. ENMC International Consortium on Myotubular Myopathy. European Neuro-Muscular Center","volume":"6","author":"Laporte","year":"1997","journal-title":"Hum. Mol. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1002\/(SICI)1098-1004(199910)14:4<320::AID-HUMU7>3.0.CO;2-O","article-title":"Identification of novel mutations in the MTM1 gene causing severe and mild forms of X-linked myotubular myopathy","volume":"14","author":"Biancalana","year":"1999","journal-title":"Hum. Mutat."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/s41588-021-01010-x","article-title":"GestaltMatcher facilitates rare disease matching using facial phenotype descriptors","volume":"54","author":"Hsieh","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/0960-8966(91)90096-B","article-title":"X-linked centronuclear myopathy: Mapping the gene to Xq28","volume":"1","author":"Grimm","year":"1991","journal-title":"Neuromuscul. Disord."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0960-8966(98)00090-X","article-title":"Characterization of 34 novel and six known MTM1 gene mutations in 47 unrelated X-linked myotubular myopathy patients","volume":"9","author":"Tanner","year":"1999","journal-title":"Neuromuscul. Disord."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1093\/hmg\/6.9.1499","article-title":"Characterization of mutations in the myotubularin gene in twenty six patients with X-linked myotubular myopathy","volume":"6","author":"Zhao","year":"1997","journal-title":"Hum. Mol. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e182","DOI":"10.1212\/NXG.0000000000000182","article-title":"A novel intronic mutation in MTM1 detected by RNA analysis in a case of X-linked myotubular myopathy","volume":"3","author":"Gonorazky","year":"2017","journal-title":"Neurol. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.nmd.2016.02.004","article-title":"Novel findings associated with MTM1 suggest a higher number of female symptomatic carriers","volume":"26","author":"Savarese","year":"2016","journal-title":"Neuromuscul. Disord."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/1090-3798(98)01004-9","article-title":"X-linked myotubular myopathy. A long-term follow-up study","volume":"2","author":"Barth","year":"1998","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.nmd.2006.07.020","article-title":"Extreme phenotypic variability in a German family with X-linked myotubular myopathy associated with E404K mutation in MTM1","volume":"16","author":"Hoffjan","year":"2006","journal-title":"Neuromuscul. Disord."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Amoasii, L., Bertazzi, D.L., Tronch\u00e8re, H., Hnia, K., Chicanne, G., Rinaldi, B., Cowling, B.S., Ferry, A., Klaholz, B., and Payrastre, B. (2012). Phosphatase-dead myotubularin ameliorates X-linked centronuclear myopathy phenotypes in mice. PLoS Genet., 8.","DOI":"10.1371\/journal.pgen.1002965"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.nmd.2007.03.010","article-title":"Myofiber size correlates with MTM1 mutation type and outcome in X-linked myotubular myopathy","volume":"17","author":"Pierson","year":"2007","journal-title":"Neuromuscul. Disord."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/s41431-020-00715-7","article-title":"Pathogenic deep intronic MTM1 variant activates a pseudo-exon encoding a nonsense codon resulting in severe X-linked myotubular myopathy","volume":"29","author":"Bryen","year":"2021","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Paila, U., Chapman, B.A., Kirchner, R., and Quinlan, A.R. (2013). GEMINI: Integrative exploration of genetic variation and genome annotations. PLoS Comput. Biol., 9.","DOI":"10.1371\/journal.pcbi.1003153"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1016\/j.nmd.2017.10.005","article-title":"The 2018 version of the gene table of monogenic neuromuscular disorders (nuclear genome)","volume":"27","author":"Bonne","year":"2017","journal-title":"Neuromuscul. Disord."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1002\/humu.20880","article-title":"Sequence variant classification and reporting: Recommendations for improving the interpretation of cancer susceptibility genetic test results","volume":"29","author":"Plon","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1002\/(SICI)1098-1004(200001)15:1<7::AID-HUMU4>3.0.CO;2-N","article-title":"Mutation nomenclature extensions and suggestions to describe complex mutations: A discussion","volume":"15","author":"Antonarakis","year":"2000","journal-title":"Hum. Mutat."},{"key":"ref_42","unstructured":"Dubowitz, V., Sewry, C.A., and Oldfors, A. (2020). Muscle Biopsy. A Practical Approach, SAUNDERS Elsevier. [5th ed.]. Printed in China."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/12\/2174\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:37:01Z","timestamp":1760132221000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/12\/2174"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,3]]},"references-count":42,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["genes14122174"],"URL":"https:\/\/doi.org\/10.3390\/genes14122174","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2023,12,3]]}}}