Lupski et al. (1991) found a DNA duplication on chromosome 17p as the apparent basis of Charcot-Marie-Tooth disease type 1A (CMT1A; 118220). They showed complete linkage and association of this duplication in 7 multigenerational CMT1A pedigrees and in several isolated, unrelated patients. Pulsed field gel electrophoresis of genomic DNA from CMT1 patients of different ethnic origins showed a novel SacII fragment of 500 kb, and this fragment showed mendelian inheritance. The duplication was also directly visualized by 2-color FISH in interphase nuclei. Lupski et al. (1991) found that a severely affected person, the product of a first-cousin marriage (Killian and Kloepfer, 1979), was homozygous for the duplication. Onset was before age 1 year and reduction in motor nerve conduction velocity was severe. A less severely affected sister was heterozygous for the duplication. The finding implicated a local DNA duplication, a segmental trisomy, as a novel mechanism for an autosomal dominant human disease. The classic example of a DNA duplication is the Bar locus in Drosophila melanogaster as described by Bridges (1936). Lupski et al. (1991) noted that failure to recognize the molecular duplication could lead to misinterpretation of marker genotypes for affected persons with identification of false recombinance and incorrect localization of the disease locus. The duplication was likewise demonstrated by Raeymaekers et al. (1991) who, like Lupski et al. (1991), concluded that the duplication is probably the mutation responsible for the disease. The duplication was demonstrated in locus D17S122 (probe VAW409R3).
Using pulsed field gel electrophoresis analysis, Hoogendijk et al. (1991) estimated the minimal size of the duplicated region in CMT1A patients to be 1,100 kb.
While trying to determine the size of the chromosome 17 duplication, Raeymaekers et al. (1992) showed that on the genetic map the duplicated markers span a minimal distance of 10 cM, while on the physical map they are present in the same NotI restriction fragment of 1,150 kb. The discrepancy between the genetic and physical map distances suggests that the 17p11.2 region is highly prone to recombination. The authors suggested that the high recombination rate may be a contributing factor to the genetic instability of the region.
Valentijn et al. (1992) used 2-color fluorescence in situ hybridization (FISH) on interphase nuclei of fibroblasts to demonstrate that the duplication is a direct tandem repeat: they observed red-green for the normal chromosome and red-green-red-green for the chromosome with the duplication; in none of the nuclei analyzed was the order red-green-green-red or green-red-red-green, compatible with an inverted repeat. The authors suggested that those affected families in which there is no duplication of the PMP22 gene likely represent intragenic mutations comparable to those in the Trembler mouse.
Hoogendijk et al. (1992) found the chromosome 17 duplication as a de novo mutation in 9 of 10 sporadic patients with HMSN I. During a population survey of CMT1 in south Wales, MacMillan et al. (1992) found duplication of locus D17S122, recognized by a DNA probe that detects an MspI polymorphism, in 10 of 11 families selected only by clinical criteria. Trisomy for this chromosome region is demonstrated either by the presence of 3 alleles or a dosage effect when only 2 of the alleles are present. The 1 family without trisomy did not differ in type or severity of disease from the other families. Lupski et al. (1992) described a patient with a cytogenetically visible duplication, dup(17)(p11.2p12). Molecular analysis demonstrated that this patient had duplications of all the DNA markers duplicated in other cases of CMT1A as well as of markers both proximal and distal to the CMT1A duplication. Upadhyaya et al. (1993) reported another instance of a microscopically visible duplication of 17p12-p11.2 in association with CMT1A.
Wise et al. (1993) used 3 molecular methods to search for the CMT1A DNA duplication in 75 unrelated patients diagnosed clinically with CMT and evaluated by electrophysiologic methods. The CMT1A duplication was found in 68% of the 63 unrelated CMT patients with electrophysiologic studies consistent with CMT type 1. The CMT1A duplication was detected as a de novo event in 2 CMT1 families. Twelve CMT patients who did not have decreased nerve conduction velocities consistent with a diagnosis of CMT type 2 were found not to have the CMT1A duplication. The most informative molecular method was the detection of the CMT1A duplication-specific junction fragment by pulsed field gel electrophoresis. Given the high frequency of the CMT1A duplication in CMT patients and the high frequency of new mutations, Wise et al. (1993) concluded that a molecular test for the CMT1A DNA duplication is useful in the differential diagnosis of patients with peripheral neuropathies.
In a 2-year-old boy with severe demyelinating CMT, Meggouh et al. (2005) identified compound heterozygosity for 2 mutations: the PMP22 duplication and a mutation in the LITAF gene (G112S; 603795.0001), which causes CMT1C (601098). Each parent was heterozygous for 1 of the mutations, and each had pes cavus and reduced nerve conduction velocities consistent with mild CMT. Meggouh et al. (2005) concluded that the cooccurrence of both mutations resulted in the more severe phenotype in the proband.
In 3 members of a 4-generation family with Roussy-Levy syndrome (180800), Auer-Grumbach et al. (1998) identified the CMT1A PMP22 duplication.
Miltenberger-Miltenyi et al. (2009) identified the CMT1A PMP22 1.4-Mb duplication in 79 (31.6%) of 250 unrelated Austrian patients with CMT.
