title: Dominant GDAP1 mutations cause predominantly mild CMT phenotypes.
abstract: OBJECTIVE
  Ganglioside-induced differentiation associated-protein 1 (GDAP1) mutations are commonly associated with autosomal recessive Charcot-Marie-Tooth (ARCMT) neuropathy; however, in rare instances, they also lead to autosomal dominant Charcot-Marie-Tooth (ADCMT). We aimed to investigate the frequency of disease-causing heterozygous GDAP1 mutations in ADCMT and their associated phenotype.
  
  
  METHODS
  We performed mutation analysis in a large cohort of ADCMT patients by means of bidirectional sequencing of coding regions and exon-intron boundaries of GDAP1. Intragenic GDAP1 deletions were excluded using an allele quantification assay. We confirmed the pathogenic character of one sequence variant by in vitro experiments assaying mitochondrial morphology and function.
  
  
  RESULTS
  In 8 Charcot-Marie-Tooth disease (CMT) families we identified 4 pathogenic heterozygous GDAP1 mutations, 3 of which are novel. Three of the mutations displayed reduced disease penetrance. Disease onset in the affected individuals was variable, ranging from early childhood to adulthood. Disease progression was slow in most patients and overall severity milder than typically seen in autosomal recessive GDAP1 mutations. Electrophysiologic changes are heterogeneous but compatible with axonal neuropathy in the majority of patients.
  
  
  CONCLUSIONS
  With this study, we broaden the phenotypic and genetic spectrum of autosomal dominant GDAP1-associated neuropathies. We show that patients with dominant GDAP1 mutations may display clear axonal CMT, but may also have only minimal clinical and electrophysiologic abnormalities. We demonstrate that cell-based functional assays can be reliably used to test the pathogenicity of unknown variants. We discuss the implications of phenotypic variability and the reduced penetrance of autosomal dominant GDAP1 mutations for CMT diagnostic testing and counseling.
authors.affiliation: VIB Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Zimoń
authors.forename: J
authors.initials: J
authors.lastname: Baets
authors.forename: G M
authors.initials: GM
authors.lastname: Fabrizi
authors.forename: E
authors.initials: E
authors.lastname: Jaakkola
authors.forename: D
authors.initials: D
authors.lastname: Kabzińska
authors.forename: J
authors.initials: J
authors.lastname: Pilch
authors.forename: A B
authors.initials: AB
authors.lastname: Schindler
authors.forename: D R
authors.initials: DR
authors.lastname: Cornblath
authors.forename: K H
authors.initials: KH
authors.lastname: Fischbeck
authors.forename: M
authors.initials: M
authors.lastname: Auer-Grumbach
authors.forename: C
authors.initials: C
authors.lastname: Guelly
authors.forename: N
authors.initials: N
authors.lastname: Huber
authors.forename: E
authors.initials: E
authors.lastname: De Vriendt
authors.forename: V
authors.initials: V
authors.lastname: Timmerman
authors.forename: U
authors.initials: U
authors.lastname: Suter
authors.forename: I
authors.initials: I
authors.lastname: Hausmanowa-Petrusewicz
authors.forename: A
authors.initials: A
authors.lastname: Niemann
authors.forename: A
authors.initials: A
authors.lastname: Kochański
authors.forename: P
authors.initials: P
authors.lastname: De Jonghe
authors.forename: A
authors.initials: A
authors.lastname: Jordanova
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology; D019556:COS Cells; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002522:Chlorocebus aethiops; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005799:Genes, Dominant; D006239:Haplotypes; D006367:HeLa Cells; D006801:Humans; D007438:Introns / Q000235:genetics; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010334:Paternity; D010375:Pedigree; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C118663:GDAP protein; D009419:Nerve Tissue Proteins