Adele D'Amico1, Fabiana Fattori2, Giorgio Tasca3, Stefania Petrini4, Francesca Gualandi5, Alessandro Bruselles6, Valentina D'Oria4, Margherita Verardo2, Rosalba Carrozzo2, Marcello Niceta7, Bjarne Udd8, Alessandra Ferlini5, Marco Tartaglia7, Enrico Bertini2. 1. Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, Rome, Italy. Electronic address: adele2.damico@opbg.net. 2. Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, Rome, Italy. 3. Institute of Neurology, Catholic University, Rome, Italy. 4. Confocal Microscopy Core Facility, Research Laboratories, Bambino Gesù Children's Hospital, Rome, Italy. 5. Department of Medical Sciences, Logistic Unit of Medical Genetics, University-Hospital of Ferrara, Italy. 6. Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy. 7. Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy. 8. Folkhälsan Institute of Genetics, Medicum, University of Helsinki, Helsinki, Finland.
Abstract
BACKGROUND: Collagen VI-related disorders (COL6-RD) are a group of heterogenous muscular diseases due to mutations in the COL6A1, COL6A2 and COL6A3 genes, encoding for collagen VI, a critical component of the extracellular matrix. Ullrich congenital muscle disorder and Bethlem myopathy represent the ends of a clinical spectrum that includes intermediate phenotypes of variable severity. UCMD are caused by recessive loss of function mutations or de-novo dominant-negative mutations. The intermediate phenotype and BM are more commonly caused by dominantly acting mutations, and less commonly by recessive mutations. Recently parental mosaicism for dominant mutations in COL6 have been reported in four COL6-RD families and germinal mosaicism has been also identified in a family with recurrence of UCMD in two half-sibs. METHODS AND RESULTS: Here we report three unrelated patients affected by a COL6-RD who carried de novo mosaic mutations in COL6A genes. These mutations, missed by Sanger sequencing, were identified by next generation sequencing. CONCLUSIONS: This report highlights the importance of a complete diagnostic workup when clinical and histological finding are consistent with a COL6-RD and strengthen the impression that mosaicisms are underestimated events underlying COL6-RD.
BACKGROUND: Collagen VI-related disorders (COL6-RD) are a group of heterogenous muscular diseases due to mutations in the COL6A1, COL6A2 and COL6A3 genes, encoding for collagen VI, a critical component of the extracellular matrix. Ullrich congenital muscle disorder and Bethlem myopathy represent the ends of a clinical spectrum that includes intermediate phenotypes of variable severity. UCMD are caused by recessive loss of function mutations or de-novo dominant-negative mutations. The intermediate phenotype and BM are more commonly caused by dominantly acting mutations, and less commonly by recessive mutations. Recently parental mosaicism for dominant mutations in COL6 have been reported in four COL6-RD families and germinal mosaicism has been also identified in a family with recurrence of UCMD in two half-sibs. METHODS AND RESULTS: Here we report three unrelated patients affected by a COL6-RD who carried de novo mosaic mutations in COL6A genes. These mutations, missed by Sanger sequencing, were identified by next generation sequencing. CONCLUSIONS: This report highlights the importance of a complete diagnostic workup when clinical and histological finding are consistent with a COL6-RD and strengthen the impression that mosaicisms are underestimated events underlying COL6-RD.
Authors: Lyudmila H Pastushkova; Vasily B Rusanov; Anna G Goncharova; Alexander G Brzhozovskiy; Alexey S Kononikhin; Anna G Chernikova; Daria N Kashirina; Andrey M Nosovsky; Roman M Baevsky; Evgeny N Nikolaev; Irina M Larina Journal: BMC Syst Biol Date: 2019-03-05
Authors: Sergey N Bardakov; Roman V Deev; Raisat M Magomedova; Zoya R Umakhanova; Valérie Allamand; Corine Gartioux; Kamil Z Zulfugarov; Patimat G Akhmedova; Vadim A Tsargush; Angelina A Titova; Mikhail O Mavlikeev; Vadim L Zorin; Ekaterina N Chernets; Gimat D Dalgatov; Fedor A Konovalov; Artur A Isaev Journal: J Neuromuscul Dis Date: 2021