title: Novel findings associated with MTM1 suggest a higher number of female symptomatic carriers.
abstract: Mutations in the MTM1 gene cause X-linked myotubular myopathy (XLMTM), characterized by neonatal hypotonia and respiratory failure, and are responsible for a premature mortality in affected males. Female carriers are usually asymptomatic but they may present with muscular weakness because of a hypothesized skewed pattern of X-chromosome inactivation. By combining next generation sequencing (NGS) and CGH array approaches, we have investigated the role of MTM1 variants in a large cohort of undiagnosed patients with a wide spectrum of myopathies. Seven novel XLMTM patients have been identified, including two girls with an unremarkable family history for myotubular myopathy. Moreover, we have detected and finely mapped a large deletion causing a myotubular myopathy with abnormal genital development. Our data confirm that the severe neonatal onset of the disease in male infants is sufficient to address the direct molecular testing toward the MTM1 gene and, above all, suggest that the number of undiagnosed symptomatic female carriers is probably underestimated.
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università di Napoli, Napoli, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Savarese
authors.affiliation: Dipartimento di Neuroscienze, Università degli Studi di Messina, Messina, Italy.
authors.forename: Olimpia
authors.initials: O
authors.lastname: Musumeci
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università di Napoli, Napoli, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Giugliano
authors.affiliation: IRCCS Fondazione Stella Maris, Pisa, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Rubegni
authors.affiliation: IRCCS Fondazione Stella Maris, Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fiorillo
authors.affiliation: IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Fattori
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università di Napoli, Napoli, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
authors.forename: Annalaura
authors.initials: A
authors.lastname: Torella
authors.affiliation: IRCCS Fondazione Stella Maris, Pisa, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Battini
authors.affiliation: Dipartimento di Neuroscienze, Università degli Studi di Messina, Messina, Italy.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Rodolico
authors.affiliation: A.O.R.N.A. Cardarelli, Napoli, Italy.
authors.forename: Aniello
authors.initials: A
authors.lastname: Pugliese
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università di Napoli, Napoli, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Piluso
authors.affiliation: Dipartimento di Neuroscienze, Istituto Besta, Milano, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Maggi
authors.affiliation: IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy.
authors.forename: Adele
authors.initials: A
authors.lastname: D'Amico
authors.affiliation: Center of Myology and Neurodegenerative Disorders, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Bruno
authors.affiliation: IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.affiliation: IRCCS Fondazione Stella Maris, Pisa, Italy.
authors.forename: Filippo Maria
authors.initials: FM
authors.lastname: Santorelli
authors.affiliation: Dipartimento di Neuroscienze, Istituto Besta, Milano, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Mora
authors.affiliation: Dipartimento di Neuroscienze, Università degli Studi di Messina, Messina, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Toscano
authors.affiliation: Center of Myology and Neurodegenerative Disorders, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Minetti
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università di Napoli, Napoli, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy. Electronic address: vinnigro@gmail.com.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Nigro
mesh_terms: D000328:Adult; D001706:Biopsy; D015153:Blotting, Western; D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007866:Leg / Q000000981:diagnostic imaging / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging / Q000473:pathology; D009135:Muscular Diseases / Q000235:genetics; D009154:Mutation; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics*; D012727:Sex Characteristics
chemical_list: D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin
keywords: Abnormal genital development; CGH array; MTM1 gene; Next-generation sequencing; X-linked myotubular myopathy