Atypical CMTIA duplications in a large cohort of CMTIA families

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(Oral presentation at the Awtwerp Consortium July 2009)

Atypical CMTIA duplications in a large cohort of CMTIA families.

P. Seeman\ E. Vyhmilkova\ J. Posadka\ R. Mazanec2 and I. Sakmaryova'

IDNA laboratory Department of Child Neurology, 'Department of Neurology, 2 "

School of Medicine, University, Prague, Czech Republic.

CMT lA is by far the most common type of inherited neuropathy. Typically it is

caused by a submicroscopic tandem duplication of a 14 Mb region on chromosome

17p112-12 around the causal, dosage sensitive gene PMP22. This genomic

rearrangement is mediated by two

highly homologous repetitive elements flanking the region resulting in a uniform

size of the duplicated region.

CMTlA duplication challenged the diagnostic methods since its discovery and a

many detection methods were described each having some limitations.

We use a set of 16 microsatelite markers within the duplicated region which is

combined with real time quantitative PCR and recently also MLPA in rare, unusual

cases. Smaller, atypical CMTIA duplication were also rarely reported in the

literature, but its relative frequency is unknown.

We report results from 12 years diagnostics of CMTlA duplication of HNPP

deletion in Czech Republic and provide evidence that CMTlA duplications may be

more frequent, than we might think. Since 1998 we confiImed the CMTlA

duplication in 519 patients flom 291 unrelated

families and the HNPP deletion in 302 patients flom 168 unrelated families.

From this large cohort we detected 6 unrelated families where some of the

markers from the CMTIA region showed non-duplicated pattern reflecting an

atypical size of the duplication. In all these

families MLPA and Q-RT-PCR showed 3 copies of entire PMP22 gene. Microsatelite

analysis showed that each family carry a duplication of different size, in five

families it was a smaller region and in one family the duplication was complex

with some regions of three

copies, some of two copies and part even only one copy - deleted.

In conclusion: in more than 2 % of cases CMTIA duplication may be of atypical

size and it must be mediated by other mechanisms or regions than the

REP-elements. Such cases would probably be missed by methods using only the

junction fragment detection. Use of enough

microsatelite markers is necessary for reliable detection of all CMTlA

duplication and additional methods as MLPA or Q-RT-PCR should be available in

the laboratory for atypical cases.