title: Mutation update: the spectra of nebulin variants and associated myopathies.
abstract: A mutation update on the nebulin gene (NEB) is necessary because of recent developments in analysis methodology, the identification of increasing numbers and novel types of variants, and a widening in the spectrum of clinical and histological phenotypes associated with this gigantic, 183 exons containing gene. Recessive pathogenic variants in NEB are the major cause of nemaline myopathy (NM), one of the most common congenital myopathies. Moreover, pathogenic NEB variants have been identified in core-rod myopathy and in distal myopathies. In this update, we present the disease-causing variants in NEB in 159 families, 143 families with NM, and 16 families with NM-related myopathies. Eighty-eight families are presented here for the first time. We summarize 86 previously published and 126 unpublished variants identified in NEB. Furthermore, we have analyzed the NEB variants deposited in the Exome Variant Server (http://evs.gs.washington.edu/EVS/), identifying that pathogenic variants are a minor fraction of all coding variants (∼7%). This indicates that nebulin tolerates substantial changes in its amino acid sequence, providing an explanation as to why variants in such a large gene result in relatively rare disorders. Lastly, we discuss the difficulties of drawing reliable genotype-phenotype correlations in NEB-associated disease.
authors.affiliation: The Folkhälsan Institute of Genetics and the Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Vilma-Lotta
authors.initials: VL
authors.lastname: Lehtokari
authors.forename: Kirsi
authors.initials: K
authors.lastname: Kiiski
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Sandaradura
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Laporte
authors.forename: Pauliina
authors.initials: P
authors.lastname: Repo
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Frey
authors.forename: Kati
authors.initials: K
authors.lastname: Donner
authors.forename: Minttu
authors.initials: M
authors.lastname: Marttila
authors.forename: Carol
authors.initials: C
authors.lastname: Saunders
authors.forename: Peter G
authors.initials: PG
authors.lastname: Barth
authors.forename: Johan T
authors.initials: JT
authors.lastname: den Dunnen
authors.forename: Alan H
authors.initials: AH
authors.lastname: Beggs
authors.forename: Nigel F
authors.initials: NF
authors.lastname: Clarke
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: North
authors.forename: Nigel G
authors.initials: NG
authors.lastname: Laing
authors.forename: Norma B
authors.initials: NB
authors.lastname: Romero
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Winder
authors.forename: Katarina
authors.initials: K
authors.lastname: Pelin
authors.forename: Carina
authors.initials: C
authors.lastname: Wallgren-Pettersson
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002889:Chromosomes, Human, Pair 2; D030541:Databases, Genetic; D005091:Exons; D005838:Genotype; D006801:Humans; D023421:Models, Animal; D009124:Muscle Proteins / Q000235:genetics*; D009135:Muscular Diseases / Q000145:classification / Q000235:genetics*; D009154:Mutation; D010641:Phenotype
chemical_list: D009124:Muscle Proteins; C035620:nebulin
keywords: NEB; actin-myosin; nebulin; nemaline (rod) myopathy; sarcomere