In our previous study published in Clinical Genetics we estimated the frequency of the 1.4-Mb CMT1Aduplication in the Greek population at 25.9%, a figure significantly lower than reports from most other populations. We noted at the time that the reduced sensitivity of the long polymerase chain reaction (PCR) method used for detecting the duplication may have been partly responsible for underestimating the duplication frequency (1).To re-evaluate the duplication frequency with a method that is almost 100% sensitive, we screened 128 consecutive Greek CMT1 index cases presenting from 2006 to 2013 using Multiplex Ligation-dependent Probe Amplification (MLPA) (2, 3). Inclusion criteria were similar to our previous study (1). Seventy-eight cases were familial (60.9%) and 50 non-familial (39.1%). Informed consent was obtained from all participants.The duplication frequency using MLPA was 52.3%, higher than our previous estimation (p = 0.0001) and similar to frequencies reported in most populations (1). In familial cases the frequency was 66.6% (52/78) and in non-familial cases 30% (15/50). Subsequent screening of the 128 cases with long PCR revealed an overall sensitivity of 67.16%, lower than figures quoted in the literature (84-87%) (2, 4). In familial cases the sensitivity was lower (59.6%) compared to non-familial cases (93.3%, p = 0.014). This indicates that in familial Greek CMT1A cases the recombination event has ∼40% possibility of occurring outside the usual 3.2-kb recombination hotspot, rather than the usually quoted figure of <25%, possibly because of relative genetic isolation (5). In the Greek population, therefore, the sensitivity of long PCR depends on the characteristics of the patient sample. The more familial cases the lower the sensitivity. Given a 75.3% of familial cases in our original sample, this largely explains our earlier underestimation of the duplication frequency (1). In conclusion, a more accurate estimation of the CMT1A-duplication frequency in Greek patients is ∼50%, similar to other ethnic populations.
There has been limited information from population studies regarding the overall frequency of the common 1.5-Mb 17p11.2 deletion and even scarcer data regarding the overall frequency of PMP22 micromutations in patients with a clinical suspicion of hereditary neuropathy with liability to pressure palsies (HNPP). We have analysed 100 consecutive Greek patients referred for HNPP genetic testing over a 15-year period to our Neurogenetics Unit in Athens, a reference centre for all regions of Greece. All patients were screened for the 1.5-Mb deletion and a selected subgroup of deletion-negative patients for PMP22 micromutations. Mutation-positive and mutation-negative patients were compared for various clinical parameters. In total, 54 mutation-positive patients were identified. In index cases, the deletion frequency was 47.8%, and the PMP22 micromutation frequency was 2.2%. Within mutation-positive patients, the common deletion represented 95.7% and PMP22 micromutations 4.3% of cases. Two previously reported PMP22 micromutations (c.364_365delCC and c.79-2A>G) were detected. HNPP index cases had a 2.8-1 male-to-female ratio, similar to mutation-negative patients. A typical phenotype (recurrent or isolated palsies) was present in 82.4% of symptomatic HNPP cases, significantly higher than mutation-negative patients. Sensitivity of proposed electrophysiological diagnostic criteria for HNPP was calculated at 95.7% and specificity at 80.5%. In conclusion, the common HNPP deletion accounts for ∼50% and PMP22 micromutations for ∼2% of cases in a large consecutive cohort of patients with suspected HNPP. The mutational and phenotypic spectrum of HNPP is similar in the Greek population compared with other populations. Proposed electrophysiological diagnostic criteria perform satisfactorily in everyday clinical practice.
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