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Here, we characterize three previously unknown variants in <jats:italic>PMP22<\/jats:italic> and assess their effect on the recently described potential CMT biomarkers\u2019 growth differentiation factor 15 (GDF15) and neurofilament light (NFL): first, a heterozygous <jats:italic>PMP22<\/jats:italic> c.178G\u2009&gt;\u2009A (p.Glu60Lys) in one mother-son pair with adult-onset mild axonal neuropathy. The variant led to abnormal splicing, confirmed in fibroblasts by reverse transcription PCR. Second, a de novo <jats:italic>PMP22<\/jats:italic> c.35A\u2009&gt;\u2009C (p.His12Pro), and third, a heterozygous 3.2\u00a0kb deletion predicting loss of exon 4. The latter two had severe CMT and ultrasonography showing strong nerve enlargement similar to a previous case of exon 4 loss due to a larger deletion. We further studied patients with <jats:italic>PMP22<\/jats:italic> duplication (CMT1A) finding slightly elevated plasma NFL, as measured by the single molecule array immunoassay (SIMOA). In addition, plasma GDF15, as measured by ELISA, correlated with symptom severity for CMT1A. However, in the severely affected individuals with <jats:italic>PMP22<\/jats:italic> exon 4 deletion or p.His12Pro, these biomarkers were within the range of variability of CMT1A and controls, although they had more pronounced nerve hypertrophy. This study adds p.His12Pro and confirms <jats:italic>PMP22<\/jats:italic> exon 4 deletion as causes of severe CMT, whereas the previously unknown splice variant p.Glu60Lys leads to mild axonal neuropathy. Our results suggest that GDF15 and NFL do not distinguish CMT1A from advanced hypertrophic neuropathy caused by rare <jats:italic>PMP22<\/jats:italic> variants.<\/jats:p>","DOI":"10.1007\/s10048-023-00729-5","type":"journal-article","created":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T11:02:37Z","timestamp":1692702157000},"page":"291-301","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Rare PMP22 variants in mild to severe neuropathy uncorrelated to plasma GDF15 or neurofilament light"],"prefix":"10.1007","volume":"24","author":[{"given":"Edouard","family":"Palu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julius","family":"J\u00e4rvilehto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jana","family":"Pennonen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadine","family":"Huber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanna-Kaisa","family":"Herukka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annakaisa","family":"Haapasalo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pirjo","family":"Isohanni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henna","family":"Tyynismaa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mari","family":"Auranen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5178-0703","authenticated-orcid":false,"given":"Emil","family":"Ylikallio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,8,22]]},"reference":[{"issue":"5","key":"729_CR1","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1097\/WCO.0000000000000474","volume":"30","author":"D Pareyson","year":"2017","unstructured":"Pareyson D, Saveri P, Pisciotta C (2017) New developments in Charcot-Marie-Tooth neuropathy and related diseases. 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