MORC2 mutations cause axonal Charcot-Marie-Tooth disease with pyramidal signs

Obaid M. Albulym, Marina L. Kennerson, Matthew B. Harms, Alexander P. Drew, Anna H. Siddell, Michaela Auer-Grumbach, Alan Pestronk, Anne Connolly, Robert H. Baloh, Stephan Zuchner, Stephen W. Reddel, Garth A. Nicholson

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Objective To use linkage analysis and whole exome sequencing to identify the genetic mutation in a multigenerational Australian family with Charcot-Marie-Tooth disease type 2 (CMT2) and pyramidal signs. Methods Genome-wide linkage analysis was performed to map the locus. Whole exome sequencing was undertaken on selected individuals (3 affected, 1 normal), and segregation analysis and mutation screening were carried out using high-resolution melt analysis. The database was queried to identify additional families with mutations. Results Significant linkage (2-point LOD score ≥ +3) and haplotype analysis mapped a new locus for CMT2 and pyramidal signs to a 6.6Mb 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 2 unrelated early onset CMT2 families and a second mutation p.E236G in 2 unrelated CMT2 families. Both the mutations occurred at highly conserved amino acid residues and were absent in the normal population. Interpretation We 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.

Original languageEnglish
Pages (from-to)419-427
Number of pages9
JournalAnnals of neurology
Issue number3
StatePublished - Mar 1 2016


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