{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T07:32:55Z","timestamp":1790839975608,"version":"4.1.0"},"reference-count":43,"publisher":"BMJ","issue":"10","funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["CoFin Regione Lombardia (n. 96)"],"award-info":[{"award-number":["CoFin Regione Lombardia (n. 96)"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["RF-2011-02347127"],"award-info":[{"award-number":["RF-2011-02347127"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Neurol Neurosurg Psychiatry"],"accepted":{"date-parts":[[2019,5,17]]},"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Inherited peripheral neuropathies (IPNs) represent a broad group of genetically and clinically heterogeneous disorders, including axonal Charcot-Marie-Tooth type 2 (CMT2) and hereditary motor neuropathy (HMN). Approximately 60%\u201370% of cases with HMN\/CMT2 still remain without a genetic diagnosis. Interestingly, mutations in HMN\/CMT2 genes may also be responsible for motor neuron disorders or other neuromuscular diseases, suggesting a broad phenotypic spectrum of clinically and genetically related conditions. Thus, it is of paramount importance to identify novel causative variants in HMN\/CMT2 patients to better predict clinical outcome and progression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We designed a collaborative study for the identification of variants responsible for HMN\/CMT2. We collected 15 HMN\/CMT2 families with evidence for autosomal recessive inheritance, who had tested negative for mutations in 94 known IPN genes, who underwent whole-exome sequencing (WES) analyses. Candidate genes identified by WES were sequenced in an additional cohort of 167 familial or sporadic HMN\/CMT2 patients using next-generation sequencing (NGS) panel analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Bioinformatic analyses led to the identification of novel or very rare variants in genes, which have not been previously associated with HMN\/CMT2 (<jats:italic>ARHGEF28<\/jats:italic>,<jats:italic>KBTBD13<\/jats:italic>,<jats:italic>AGRN<\/jats:italic>and<jats:italic>GNE<\/jats:italic>); in genes previously associated with HMN\/CMT2 but in combination with different clinical phenotypes (<jats:italic>VRK1<\/jats:italic>and<jats:italic>PNKP<\/jats:italic>), and in the<jats:italic>SIGMAR1<\/jats:italic>gene, which has been linked to HMN\/CMT2 in only a few cases. These findings were further validated by Sanger sequencing, segregation analyses and functional studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These results demonstrate the broad spectrum of clinical phenotypes that can be associated with a specific disease gene, as well as the complexity of the pathogenesis of neuromuscular disorders.<\/jats:p><\/jats:sec>","DOI":"10.1136\/jnnp-2019-320717","type":"journal-article","created":{"date-parts":[[2019,6,5]],"date-time":"2019-06-05T21:19:18Z","timestamp":1559769558000},"page":"1171-1179","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":50,"title":["Expanding the spectrum of genes responsible for hereditary motor neuropathies"],"prefix":"10.1136","volume":"90","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2546-4357","authenticated-orcid":false,"given":"Stefano 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