CMT 1A: Copy number variation upstream of PMP22

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Eur J Hum Genet. 2009 Nov 4. [Epub ahead of print]

Copy number variation upstream of PMP22 in Charcot-Marie-Tooth disease.

Weterman MA, van Ruissen F, de Wissel M, Bordewijk L, Samijn JP, van der Pol WL,

Meggouh F, Baas F.

Neurogenetics Lab, Academic Medical Center Amsterdam, Amsterdam, The

Netherlands.

In several individuals with a Charcot-Marie-Tooth (CMT) phenotype, we found a

copy number variation (CNV) on chromosome 17p12 in the direct vicinity of the

peripheral myelin protein 22 (PMP22) gene. The exact borders and size of this

CNV were determined by Southern blot analysis, MLPA, vectorette PCR, and

microarray hybridization analyses.

All patients from six apparently unrelated families carried an identical 186-kb

duplication different from the commonly reported 1.5-Mb duplication associated

with CMT1A.

This ancestral mutation that was not reported in the human structural variation

database was only detected in affected individuals and family members. It was

absent in 2124 control chromosomes and 40 patients with a chronic inflammatory

demyelinating polyneuropathy (CIDP) and therefore should be regarded as

causative for the disease.

This variant escapes most routine diagnostic screens for CMT1A, because copy

numbers of PMP22 probes were all normal. No indications were found for the

involvement of the genes that are located within this duplication. A possible

association of this duplication with a mutation in the PMP22 coding regions was

also excluded.

We suggest that this CNV proximal of the PMP22 gene leads to CMT through an

unknown mechanism affecting PMP22 expression.