title: Centronuclear myopathies: genotype-phenotype correlation and frequency of defined genetic forms in an Italian cohort.
abstract: Centronuclear myopathies (CNMs) are a group of clinically and genetically heterogeneous muscle disorders. To date, mutation in 7 different genes has been reported to cause CNMs but 30 % of cases still remain genetically undefined. Genetic investigations are often expensive and time consuming. Clinical and morphological clues are needed to facilitate genetic tests and to choose the best approach for genetic screening. We aimed to describe genotype-phenotype correlation in an Italian cohort of patients affected by CNMs, to define the relative frequencies of its defined genetic forms and to draw a diagnostic algorithm to address genetic investigations. We recruited patients with CNMs from all the Italian tertiary neuromuscular centers following clinical and histological criteria. All selected patients were screened for the four 'canonical' genes related to CNMs: MTM1, DNM2, RYR1 and BIN1. Pathogenetic mutations were found in 38 of the 54 screened patients (70 %), mostly in patients with congenital onset (25 of 30 patients, 83 %): 15 in MTM1, 6 in DNM2, 3 in RYR1 and one in TTN. Among the 13 patients with a childhood-adolescence onset, mutations were found in 6 patients (46 %), all in DNM2. In the group of the 11 patients with adult onset, mutations were identified in 7 patients (63 %), again in DNM2, confirming that variants in this gene are relatively more common in late-onset phenotypes. The present study provides the relative molecular frequency of centronuclear myopathy and of its genetically defined forms in Italy and also proposes a diagnostic algorithm to be used in clinical practice to address genetic investigations.
authors.affiliation: Unit for Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, Viale San Paolo 15, 00146, Rome, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Fattori
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Maggi
authors.forename: Claudio
authors.initials: C
authors.lastname: Bruno
authors.forename: Denise
authors.initials: D
authors.lastname: Cassandrini
authors.forename: Valentina
authors.initials: V
authors.lastname: Codemo
authors.forename: Michela
authors.initials: M
authors.lastname: Catteruccia
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tasca
authors.forename: Angela
authors.initials: A
authors.lastname: Berardinelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Magri
authors.forename: Marika
authors.initials: M
authors.lastname: Pane
authors.forename: Anna
authors.initials: A
authors.lastname: Rubegni
authors.forename: Lucio
authors.initials: L
authors.lastname: Santoro
authors.forename: Lucia
authors.initials: L
authors.lastname: Ruggiero
authors.forename: Patrizio
authors.initials: P
authors.lastname: Fiorini
authors.forename: Antonella
authors.initials: A
authors.lastname: Pini
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mongini
authors.forename: Sonia
authors.initials: S
authors.lastname: Messina
authors.forename: Giacomo
authors.initials: G
authors.lastname: Brisca
authors.forename: Irene
authors.initials: I
authors.lastname: Colombo
authors.forename: Guja
authors.initials: G
authors.lastname: Astrea
authors.forename: Chiara
authors.initials: C
authors.lastname: Fiorillo
authors.forename: Cinzia
authors.initials: C
authors.lastname: Bragato
authors.forename: Isabella
authors.initials: I
authors.lastname: Moroni
authors.forename: Elena
authors.initials: E
authors.lastname: Pegoraro
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: D'Apice
authors.forename: Enrico
authors.initials: E
authors.lastname: Alfei
authors.forename: Marina
authors.initials: M
authors.lastname: Mora
authors.forename: Lucia
authors.initials: L
authors.lastname: Morandi
authors.forename: Alice
authors.initials: A
authors.lastname: Donati
authors.forename: Anni
authors.initials: A
authors.lastname: Evilä
authors.forename: Anna
authors.initials: A
authors.lastname: Vihola
authors.forename: Bjarne
authors.initials: B
authors.lastname: Udd
authors.forename: Pia
authors.initials: P
authors.lastname: Bernansconi
authors.forename: Eugenio
authors.initials: E
authors.lastname: Mercuri
authors.forename: Filippo Maria
authors.initials: FM
authors.lastname: Santorelli
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Adele
authors.initials: A
authors.lastname: D'Amico
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D064211:Connectin / Q000235:genetics*; D034285:Dynamin II / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D020914:Myopathies, Structural, Congenital / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D055815:Young Adult
chemical_list: D064211:Connectin; D019837:Ryanodine Receptor Calcium Release Channel; C577285:TTN protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin; D034285:Dynamin II