Genome-wide linkage analysis and whole exome sequencing were used in this study to identify the genetic mutation in a multigenerational Australian family with Charcot-Marie-Tooth type 2 (CMT2) and pyramidal signs. Significant linkage (2 point LOD score ≥ +3) and haplotype analysis mapped a new locus for CMT2 and pyramidal signs to a 6.6-Mb interval on chromosome 22q12.1-q12.3. Whole exome sequencing identified a novel mutation (p.R252W) in the Microrchidia CW-type zinc finger 2 (MORC2) gene mapping within the linkage region. The mutation fully segregated with the disease phenotype in the family. Screening additional families and querying unsolved CMT2 exomes we identified the p.R252W mutation in two unrelated early onset CMT2 families and a second mutation p.E236G in two unrelated CMT2 families. Both the mutations occurred at highly conserved amino acid residues and were absent in the normal population. The authors have identified a new locus in which MORC2 mutations are the likely pathogenic cause of CMT2 and pyramidal signs in these families. MORC2 encodes the human CW-type zinc finger 2 protein which is a chromatin modifier involved in the regulation of DNA repair as well as gene transcription.
