CMT X3: Evidence of a founder haplotype refines the X-linked Charcot-Marie-Tooth

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Neurogenetics. 2008 May 6

Evidence of a founder haplotype refines the X-linked Charcot-Marie-

Tooth (CMTX3) locus to a 2.5 Mb region.

Brewer M, Changi F, Antonellis A, Fischbeck K, Polly P, Nicholson G,

Kennerson M.

Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord,

New South Wales, 2139, Australia

X-linked Charcot-Marie-Tooth (CMTX) disease is a common inherited

degenerative disorder of the peripheral nerve. Previously, our

laboratory identified a large New Zealand/United Kingdom (NZ/UK)

family mapping to the CMTX3 locus (Xq26.3-27.1). We have now

identified a second large, Australian X-linked CMT family that links

to the CMTX3 locus. This new family has the same phenotype as our

previously described CMTX3 family, with slightly milder disease in

males than CMTX1 and asymptomatic carrier females. This study also

includes the re-analysis of one of the original US pedigrees

reporting the CMTX3 locus. The large Australian family shared the

complete disease haplotype with our original NZ/UK family, while the

American family shared only the distal portion of the disease

haplotype. Comparison of the frequency of the CMTX3 haplotype to the

normal population showed strong statistical evidence (p < 0.0001)

indicating that the smaller shared haplotype is identical by descent.

This suggests that the new CMTX3 family, our previously reported

family, and the original American CMTX3 family have a common

ancestor, and the disease in these families is caused by a founder

mutation. The ancestral recombination observed in the American family

refines the CMTX3 interval to a 2.5 Mb region between DXS984 and

DXS8106. In this region, 11 out of the 15 annotated genes have been

excluded for pathogenic mutations.