Genetic dosage compensation via co-occurrence of PMP22 duplication and PMP22 deletion.

Charcot-Marie-Tooth disease type 1 A (CMT1A, OMIM #118220) and hereditary neuropathy with liability to pressure palsies (HNPP or tomaculous neu-ropathy, OMIM #162500) are autosomal dominantly inherited neuropathies caused by genomic rearrangements on chromosome 17p11.2-p12 containing PMP22. Heterozygous PMP22 duplications result in a peripheral neuropathy characterized by distal muscular atrophy, foot deformities, sensory deficits, and generally reduced nerve conduction velocities in the demyelinating range (CMT1A). In contrast, a hetero-zygous PMP22 deletion results in HNPP that is characterized by recurrent transient episodes of transient focal compressive neuropathies manifesting as weakness , sensory loss, or both, with electrophysiology showing multifocal slowing at the sites of compression. We report a large 3-generation family including several patients with CMT1A or HNPP, as well as 2 unaffected sisters, both with co-occurrence of a PMP22 duplication and a PMP22 deletion. Case report. We first examined 4 siblings (II-2, II-3, II-4, II-5, figure) of a 55-year-old female index patient (II-1) with CMT1A by performing a multiplex ligation-dependent probe amplification (MLPA) assay (Kit P033-B3, MRC-Holland, Amsterdam, Netherlands). As expected, one sister (II-4) with typical features of CMT1A carried a PMP22 duplication. MLPA analysis of another sister (II-2) who reported transient numbness of the palms and feet, probably caused by chemo-therapy, revealed a normal genotype. The second clinically unaffected sister (II-5) also had normal MLPA results. Remarkably, one brother (II-3) carried a PMP22 deletion, which was consistent with his focal neuropathic symptoms due to traumatic compression. Subsequently, further relatives were examined (figure , table e-1 on the Neurology ® Web site at Neurology.org). The father (I-1) of the siblings was deceased; further paternal family members were not available. The mother (I-2) with CMT1A carried a PMP22 duplication, as expected. The daughter (III-1) and son (III-3) of individual II-5 carried a PMP22 deletion, as did their uncle (II-3). We therefore assumed the co-occurrence of a maternally inherited PMP22 duplication and a paternally inherited PMP22 deletion in their mother (II-5). To verify this hypothesis, we performed segregation analysis with 3 polymorphic microsatellite markers (CMT 4A, CMT 9A, and CMT 9B 1) within the segment in region 17p11.2-p12 in all of the above-mentioned family members. This analysis confirmed that the unaffected sisters II-5 and II-2, both with normal MLPA results, carried the maternal duplication of PMP22 and the paternal deletion of PMP22. There was no clinical or electrophysiologic evidence for CMT1A or HNPP in the sisters (table e-1). Discussion. To our knowledge, this …