An unusual cosegregation of cmt1a duplication and hnpp PMP22 point mutation in a family with CMT1 disease

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The common CMT1A duplication and HNPP deletion arise from unequal crossing over and homologous recombination during meiosis between flanking repeats (CMT1A‐REP). CMT1A and HNPP thus result from an altered copy number of the dosage‐sensitive myelin gene PMP22 which is included in the duplicated/deleted tract. However, both diseases can also be caused by rare PMP22 point mutations. We report here a unique family carrying both the CMT1A duplication and an HNPP PMP22 point mutation. A CMT1 child (III‐1), the only affected member of her family, was found to carry the duplication. Surprisingly, the mutation was also found in the mother (II‐2) who had normal clinical and electrophysiologic phenotype. PMP22 sequence analysis in both individuals uncovered a truncating frameshift mutation (Leu145fs) in the healthy mother but not in the affected child. In the mother, this mutation, which had been previously identified by us in 3 other HNPP families, would inactivate the extra copy of the PMP22 gene, functionally compensating the effects of the duplication. Further investigations in the family demonstrated that the healthy maternal grandmother (I‐1) also carried both the duplication and the point mutation, while her other son (II‐1) had neither of them, which indicates that both mutations were harbored by the same chromosome. Microsatellite analysis suggests that a meiotic homologous recombination event has occurred in the affected child, replacing the mutated PMP22 copy with a functional one and resulting in CMT1 phenotype.