PMP22 was first reported in relation to autosomal dominant Hereditary Neuropathy with liability to Pressure Palsies (HNPP) in 1993 (Chance et al., PMID: 8422677). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we decided to split this disease with the PMP22 duplication causing Charcot Marie Tooth Type 1A and point mutations causing CMT1E. The split curation for CMT1A and CMT1E has been curated separately. The most common genetic variant associated with HNPP is a 1.5MB deletion affecting PMP22 and has been seen in many patients over time. This decreases PMP22 protein levels and affects patients through a dosage sensitive mechanism. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by animal models involving mice. In mice models with PMP22 deletion, nerves recapitulate tomacula swellings seen in HNPP patients, and decreased nerve conduction velocities. In summary, there is definitive and longstanding evidence supporting the relationship between PMP22 deletion and HNPP. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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