title: Facing the genetic heterogeneity in neuromuscular disorders: linkage analysis as an economic diagnostic approach towards the molecular diagnosis.
abstract: The identification of an ever increasing number of gene defects in patients with neuromuscular disorders has disclosed both marked phenotype and genotype variability and considerable disease overlap. In order to offer an economic strategy to characterise the molecular defect in patients with unclassified neuromuscular disorders, we designed DNA marker sets for linkage analysis of 62 distinct neuromuscular disorders gene loci, including all known muscular dystrophies, congenital myopathies, congenital myasthenic syndromes and myotonias. Genotyping of marker loci of 140 clinically well-characterised families with unclassified neuromuscular disorders reduced the number of candidates to one or two genes in 49 % of the families. Subsequent mutation analysis and genome-wide scans enabled the determination of the genetic defect in 31 % of the families including the identification of a new gene and a new mutation in an unexpected candidate gene. This highlights the effective application of this approach both for diagnostic strategies as well as for the identification of new loci and genes.
authors.affiliation: Department of Neuropaediatrics, Technical University, 01307 Dresden, Germany.
authors.forename: M
authors.initials: M
authors.lastname: von der Hagen
authors.forename: J
authors.initials: J
authors.lastname: Schallner
authors.forename: A M
authors.initials: AM
authors.lastname: Kaindl
authors.forename: K
authors.initials: K
authors.lastname: Koehler
authors.forename: P
authors.initials: P
authors.lastname: Mitzscherling
authors.forename: A
authors.initials: A
authors.lastname: Abicht
authors.forename: U
authors.initials: U
authors.lastname: Grieben
authors.forename: R
authors.initials: R
authors.lastname: Korinthenberg
authors.forename: W
authors.initials: W
authors.lastname: Kress
authors.forename: A
authors.initials: A
authors.lastname: von Moers
authors.forename: J S
authors.initials: JS
authors.lastname: Müller
authors.forename: U
authors.initials: U
authors.lastname: Schara
authors.forename: M
authors.initials: M
authors.lastname: Vorgerd
authors.forename: M C
authors.initials: MC
authors.lastname: Walter
authors.forename: C
authors.initials: C
authors.lastname: Müller-Reible
authors.forename: C
authors.initials: C
authors.lastname: Hübner
authors.forename: H
authors.initials: H
authors.lastname: Lochmüller
authors.forename: A
authors.initials: A
authors.lastname: Huebner
mesh_terms: D004252:DNA Mutational Analysis / Q000379:methods; D030541:Databases, Genetic / Q000706:statistics & numerical data; D003937:Diagnosis, Differential; D005192:Family Health; D018740:Genetic Heterogeneity; D005838:Genotype; D006801:Humans; D025202:Molecular Diagnostic Techniques / Q000191:economics / Q000379:methods*; D009124:Muscle Proteins / Q000235:genetics*; D009468:Neuromuscular Diseases / Q000145:classification / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D009124:Muscle Proteins