title: A recurrent copy number variation of the NEB triplicate region: only revealed by the targeted nemaline myopathy CGH array.
abstract: Recently, new large variants have been identified in the nebulin gene (NEB) causing nemaline myopathy (NM). NM constitutes a heterogeneous group of disorders among the congenital myopathies, and disease-causing variants in NEB are a main cause of the recessively inherited form of NM. NEB consists of 183 exons and it includes homologous sequences such as a 32-kb triplicate region (TRI), where eight exons are repeated three times (exons 82-89, 90-97, 98-105). In human, the normal copy number of NEB TRI is six (three copies in each allele). Recently, we described a custom NM-CGH microarray designed to detect copy number variations (CNVs) in the known NM genes. The array has now been updated to include all the currently known 10 NM genes. The NM-CGH array is superior in detecting CNVs, especially of the NEB TRI, that is not included in the exome capture kits. To date, we have studied 266 samples from 196 NM families using the NM-CGH microarray, and identified a novel recurrent NEB TRI variation in 13% (26/196) of the families and in 10% of the controls (6/60). An analysis of the breakpoints revealed adjacent repeat elements, which are known to predispose for rearrangements such as CNVs. The control CNV samples deviate only one copy from the normal six copies, whereas the NM samples include CNVs of up to four additional copies. Based on this study, NEB seems to tolerate deviations of one TRI copy, whereas addition of two or more copies might be pathogenic.
authors.affiliation: The Folkhälsan Institute of Genetics and The Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Kirsi
authors.initials: K
authors.lastname: Kiiski
authors.affiliation: The Folkhälsan Institute of Genetics and The Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Vilma-Lotta
authors.initials: VL
authors.lastname: Lehtokari
authors.affiliation: Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
authors.forename: Ari
authors.initials: A
authors.lastname: Löytynoja
authors.affiliation: The Folkhälsan Institute of Genetics and The Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Liina
authors.initials: L
authors.lastname: Ahlstén
authors.affiliation: The Folkhälsan Institute of Genetics and The Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Jenni
authors.initials: J
authors.lastname: Laitila
authors.affiliation: The Folkhälsan Institute of Genetics and The Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Carina
authors.initials: C
authors.lastname: Wallgren-Pettersson
authors.affiliation: The Folkhälsan Institute of Genetics and The Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.|Division of Genetics, Department of Biosciences, University of Helsinki, Helsinki, Finland.
authors.forename: Katarina
authors.initials: K
authors.lastname: Pelin
mesh_terms: D016022:Case-Control Studies; D056905:Chromosome Breakpoints; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D006801:Humans; D009124:Muscle Proteins / Q000235:genetics*; D017696:Myopathies, Nemaline / Q000235:genetics*
chemical_list: D009124:Muscle Proteins; C035620:nebulin