brain sciences Article Rare among Rare: Phenotypes of Uncommon CMT Genotypes Luca Gentile 1, * , Massimo Russo 1 , Federica Taioli 2 , Moreno Ferrarini 2 , M’Hammed Aguennouz 1 , Carmelo Rodolico 1 , Antonio Toscano 1 , Gian Maria Fabrizi 2,3 and Anna Mazzeo 1   Citation: Gentile, L.; Russo, M.; Taioli, F.; Ferrarini, M.; Aguennouz, M.; Rodolico, C.; Toscano, A.; Fabrizi, G.M.; Mazzeo, A. Rare among Rare: Phenotypes of Uncommon CMT Genotypes. Brain Sci. 2021, 11, 1616. https://doi.org/10.3390/brainsci11121616 Academic Editors: Boel De Paepe and Daman Kumari Received: 16 November 2021 Accepted: 6 December 2021 Published: 8 December 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; russom@unime.it (M.R.); aguenoz.mhommed@unime.it (M.A.); crodolico@unime.it (C.R.); antonio.toscano@unime.it (A.T.); annamazzeo@yahoo.it (A.M.) 2 Department of Neurological Sciences, Biomedicine and Movement Sciences, University of Verona, Piazzale L.A. Scuro 10, 37134 Verona, Italy; federica.taioli@univr.it (F.T.); moreno.ferrarini@univr.it (M.F.); gianmaria.fabrizi@univr.it (G.M.F.) 3 Azienda Ospedaliera Universitaria Integrata Verona—Borgo Roma, Piazzale L.A. Scuro 10, 37134 Verona, Italy * Correspondence: luca.gentile@unime.it Abstract: (1) Background: Charcot–Marie–Tooth disease (CMT) is the most frequent form of inherited chronic motor and sensory polyneuropathy. Over 100 CMT causative genes have been identified. Previous reports found PMP22, GJB1, MPZ, and MFN2 as the most frequently involved genes. Other genes, such as BSCL2, MORC2, HINT1, LITAF, GARS, and autosomal dominant GDAP1 are responsible for only a minority of CMT cases. (2) Methods: we present here our records of CMT patients harboring a mutation in one of these rare genes (BSCL2, MORC2, HINT1, LITAF, GARS, autosomal dominant GDAP1). We studied 17 patients from 8 unrelated families. All subjects underwent neurologic evaluation and genetic testing by next-generation sequencing on an Ion Torrent PGM (Thermo Fischer) with a 44-gene custom panel. (3) Results: the following variants were found: BSCL2 c.263A > G p.Asn88Ser (eight subjects), MORC2 c.1503A > T p.Gln501His (one subject), HINT1 c.110G > C p.Arg37Pro (one subject), LITAF c.404C > G p.Pro135Arg (two subjects), GARS c.1660G > A p.Asp554Asn (three subjects), GDAP1 c.374G > A p.Arg125Gln (two subjects). (4) Expanding the spectrum of CMT phenotypes is of high relevance, especially for less common variants that have a higher risk of remaining undiagnosed. The necessity of reaching a genetic definition for most patients is great, potentially making them eligible for future experimentations. Keywords: CMT; rare genes; genotype/phenotype 1. Introduction Charcot–Marie–Tooth disease (CMT) is the most frequent form of inherited chronic motor and sensory polyneuropathies and one of the most frequent genetic neuromuscular disorders, with a prevalence of 1:2500 [1]. CMT can manifest in heterogeneous ways, with variable phenotypic presentation even among subjects belonging to the same family [2]. In rare cases, the CMT phenotype could be worsened by a superimposed inflammatory process [3,4]. The classification of CMT is based on the type of inheritance (autosomal dominant, AD; autosomal recessive, AR; X-linked) and on the results of upper limb motor nerve conduction studies: CMT1, predominantly demyelinating, is characterized by nerve velocity under 38 m/s; CMT2, predominantly axonal, presents motor velocities above 38 m/s. An additional group includes intermediate CMT, with motor conduction velocities between 25 and 45 m/s [5]. Over 100 CMT causative genes have been identified. Previous reports found PMP22, GJB1, MPZ, and MFN2 as the most frequently involved genes [6–9]. Other reports of CMT patients from the Mediterranean area showed that other genes (autosomal recessive GDAP1 and HSPB1) could frequently be involved, suggesting that genetic distribution could possibly be influenced by geographical features [10–14]. It has been calculated that almost 90% of CMT patients harbor a mutation in one of the above- mentioned genes [1,15]. Other genes, such as BSCL2, MORC2, HINT1, LITAF, GARS1, Brain Sci. 2021, 11, 1616. https://doi.org/10.3390/brainsci11121616 https://www.mdpi.com/journal/brainsci