Linkage analysis and whole exome sequencing reveals AHNAK2 as a novel genetic cause for autosomal recessive CMT in a Malaysian family

Neurogenetics. 2019 Aug;20(3):117-127. doi: 10.1007/s10048-019-00576-3. Epub 2019 Apr 22.


Charcot-Marie-Tooth (CMT) disease is a form of inherited peripheral neuropathy that affects motor and sensory neurons. To identify the causative gene in a consanguineous family with autosomal recessive CMT (AR-CMT), we employed a combination of linkage analysis and whole exome sequencing. After excluding known AR-CMT genes, genome-wide linkage analysis mapped the disease locus to a 7.48-Mb interval on chromosome 14q32.11-q32.33, flanked by the markers rs2124843 and rs4983409. Whole exome sequencing identified two non-synonymous variants (p.T40P and p.H915Y) in the AHNAK2 gene that segregated with the disease in the family. Pathogenic predictions indicated that p.T40P is the likely causative allele. Analysis of AHNAK2 expression in the AR-CMT patient fibroblasts showed significantly reduced mRNA and protein levels. AHNAK2 binds directly to periaxin which is encoded by the PRX gene, and PRX mutations are associated with another form of AR-CMT (CMT4F). The altered expression of mutant AHNAK2 may disrupt the AHNAK2-PRX interaction in which one of its known functions is to regulate myelination.

Keywords: AHNAK2; Autosomal recessive CMT; Inherited neuropathy.

MeSH terms

  • Adolescent
  • Alleles
  • Biopsy
  • Charcot-Marie-Tooth Disease / genetics*
  • Chromosome Mapping
  • Consanguinity
  • Cytoskeletal Proteins / genetics*
  • Family Health
  • Female
  • Fibroblasts / metabolism
  • Genes, Recessive
  • Genetic Linkage
  • Genetic Markers
  • Genetic Predisposition to Disease*
  • Haplotypes
  • Humans
  • Lod Score
  • Loss of Heterozygosity
  • Malaysia
  • Male
  • Membrane Proteins / genetics*
  • Mutation, Missense
  • Neurons / metabolism
  • Pedigree
  • Whole Exome Sequencing


  • AHNAK2 protein, human
  • Cytoskeletal Proteins
  • Genetic Markers
  • Membrane Proteins
  • periaxin