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To address this question, the Inherited Neuropathy Consortium collected a large standardized sample of such rare CMT1A patients over a period of 8\u2009years. CMT1A is caused in most patients by a uniformly sized 1.5\u2009Mb duplication event involving the gene PMP22<\/jats:italic>.<\/jats:p><\/jats:sec>Methods<\/jats:title>We genotyped DNA samples from 971 CMT1A patients on Illumina BeadChips. Genome\u2010wide analysis was performed in a subset of 330 of these patients, who expressed the extremes of a hallmark symptom: mild and severe foot dorsiflexion strength impairment. SIPA1L2<\/jats:italic> (signal\u2010induced proliferation\u2010associated 1 like 2), the top identified candidate modifier gene, was expressed in the peripheral nerve, and our functional studies identified and confirmed interacting proteins using coimmunoprecipitation analysis, mass spectrometry, and immunocytochemistry. Chromatin immunoprecipitation and in vitro siRNA experiments were used to analyze gene regulation.<\/jats:p><\/jats:sec>Results<\/jats:title>We identified significant association of 4 single nucleotide polymorphisms (rs10910527, rs7536385, rs4649265, rs1547740) in SIPA1L2<\/jats:italic> with foot dorsiflexion strength (p<\/jats:italic> <\u20091\u2009\u00d7\u200910\u22127<\/jats:sup>). Coimmunoprecipitation and mass spectroscopy studies identified \u03b2\u2010actin and MYH9 as SIPA1L2 binding partners. Furthermore, we show that SIPA1L2<\/jats:italic> is part of a myelination\u2010associated coexpressed network regulated by the master transcription factor SOX10. Importantly, in vitro knockdown of SIPA1L2<\/jats:italic> in Schwannoma cells led to a significant reduction of PMP22<\/jats:italic> expression, hinting at a potential strategy for drug development.<\/jats:p><\/jats:sec>Interpretation<\/jats:title>\nSIPA1L2<\/jats:italic> is a potential genetic modifier of CMT1A phenotypic expressions and offers a new pathway to therapeutic interventions. ANN NEUROL 2019;85:316\u2013330.<\/jats:bold><\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.25426","type":"journal-article","created":{"date-parts":[[2019,2,1]],"date-time":"2019-02-01T07:16:37Z","timestamp":1549005397000},"page":"316-330","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Variation in SIPA1L2<\/i> is correlated with phenotype modification in Charcot\u2013 Marie\u2013 Tooth disease type 1A"],"prefix":"10.1002","volume":"85","author":[{"given":"Feifei","family":"Tao","sequence":"first","affiliation":[{"name":"Department for Human Genetics and Hussman Institute for Human Genomics University of Miami Miami FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary W.","family":"Beecham","sequence":"additional","affiliation":[{"name":"Department for Human Genetics and Hussman Institute for Human Genomics University of Miami Miami 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