{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:38:04Z","timestamp":1760146684593,"version":"build-2065373602"},"reference-count":18,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T00:00:00Z","timestamp":1733184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Objectives: Variants in Cyclin F (CCNF) have been associated to amyotrophic lateral sclerosis (ALS) and\/or frontotemporal dementia (FTD) in a group of cases. The objectives of this study were to determine the contribution of CCNF in a large cohort of Italian ALS patients, to look for genotype-phenotype correlation of the mutations and to evaluate the CCNF-associated clinical features. Methods: We applied next-generation sequencing technologies on 971 unrelated Italian ALS patients and we filtered results to look for variants in CCNF gene. Results: We identified 13 rare missense variants in 16 index cases (2 familial and 14 sporadic), with a cumulative mutational frequency of 1.6%. The most prevalent variant was p.Phe197Leu, found in three patients. The clinical presentation was heterogeneous, with a classic phenotype in eight patients, upper motor neuron dominant (UMN-D) phenotype in four patients, and flail arm in four patients. Clinical evaluation for cognitive impairment was performed in 13 patients using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) test, demonstrating that almost half of the patients (n = 6) had variable degrees of frontal dysfunction. Discussion: In our cohort, we observed CCNF variants in 1.6% of patients (16\/971), a percentage similar to that found in other series. Clinical presentation is heterogeneous, but CCNF variants are significantly associated to cognitive impairment. Conclusions: Our study expands the CCNF genetic variant spectrum in a large cohort of Italian ALS patients. Further studies are needed to assess genotype-phenotype associations of CCNF variants and to specify the role of each variant, which are quite common, especially in sALS patients.<\/jats:p>","DOI":"10.3390\/genes15121566","type":"journal-article","created":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T04:01:29Z","timestamp":1733198489000},"page":"1566","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exploring the Role of CCNF Variants in Italian ALS Patients"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7314-3393","authenticated-orcid":false,"given":"Giulia","family":"Bisogni","sequence":"first","affiliation":[{"name":"Centro Clinico NeMO Adulti, Fondazione Serena Onlus-Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amelia","family":"Conte","sequence":"additional","affiliation":[{"name":"Centro Clinico NeMO Adulti, Fondazione Serena Onlus-Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2325-4137","authenticated-orcid":false,"given":"Umberto","family":"Costantino","sequence":"additional","affiliation":[{"name":"Neurology Unit, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2891-0340","authenticated-orcid":false,"given":"Serena","family":"Lattante","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Universit\u00e0 del Salento, 73100 Lecce, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Bernardo","sequence":"additional","affiliation":[{"name":"Centro Clinico NeMO Adulti, Fondazione Serena Onlus-Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"Lucioli","sequence":"additional","affiliation":[{"name":"Centro Clinico NeMO Adulti, Fondazione Serena Onlus-Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agata Katia","family":"Patanella","sequence":"additional","affiliation":[{"name":"Centro Clinico NeMO Adulti, Fondazione Serena Onlus-Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola","family":"Cimbolli","sequence":"additional","affiliation":[{"name":"Centro Clinico NeMO Adulti, Fondazione Serena Onlus-Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elda","family":"Del Giudice","sequence":"additional","affiliation":[{"name":"Research & Innovation (R&I Genetics) Srl, 35127 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federica","family":"Vettor","sequence":"additional","affiliation":[{"name":"Research & Innovation (R&I Genetics) Srl, 35127 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6898-8882","authenticated-orcid":false,"given":"Giuseppe","family":"Marangi","sequence":"additional","affiliation":[{"name":"Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Unit of Medical Genetics, Department of Laboratory and Infectious Disease Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo Niccol\u00f2","family":"Doronzio","sequence":"additional","affiliation":[{"name":"Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Unit of Medical Genetics, Department of Laboratory and Infectious Disease Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4871-9519","authenticated-orcid":false,"given":"Marcella","family":"Zollino","sequence":"additional","affiliation":[{"name":"Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Unit of Medical Genetics, Department of Laboratory and Infectious Disease Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario","family":"Sabatelli","sequence":"additional","affiliation":[{"name":"Centro Clinico NeMO Adulti, Fondazione Serena Onlus-Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"},{"name":"Institute of Neurology, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nature20413","article-title":"Decoding ALS: From genes to mechanism","volume":"539","author":"Taylor","year":"2016","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.1056\/NEJMra1603471","article-title":"Amyotrophic Lateral Sclerosis","volume":"377","author":"Brown","year":"2017","journal-title":"N. Engl. J. 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