{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T05:48:21Z","timestamp":1788241701176,"version":"build-2803163510"},"reference-count":19,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:00:00Z","timestamp":1760140800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: CLIFAHDD syndrome (OMIM # 616266) is a rare neurodevelopmental disorder caused by mutations in the NALCN gene. It is characterized by hypotonia, developmental delay, and congenital contractures of the limbs and face. We report a 33-year-old Italian woman with a mild form of CLIFAHDD who exhibited early-onset language difficulties and mild intellectual disability and later developed gait and balance impairments in adulthood. Methods and Results: Whole Exome Sequencing (WES) identified a novel missense variant c.1514A&gt;T; p.(Lys505Met) in the NALCN gene. The allele frequency of this variant is not detected (MAF = 0.0), the variant is classified as likely pathogenic according to ACMG criteria, and predicted to be probably damaging by PolyPhen-2. It affects a critical residue within the second pore-forming domain of the NALCN channel, potentially altering lipid interactions and channel regulation. Sanger sequencing and segregation analysis confirmed the variant to be heterozygous and de novo. Conclusions: The patient\u2019s milder symptoms and later onset, compared to severe pediatric cases, suggest that the clinical spectrum of CLIFAHDD syndrome may be broader than previously recognized. These findings underscore the potential influence of mutation location on disease presentation and severity.<\/jats:p>","DOI":"10.3390\/genes16101181","type":"journal-article","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T08:10:31Z","timestamp":1760343031000},"page":"1181","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A New Variant in the NALCN Channel Is Responsible for Cerebellar Ataxia and Cognitive Impairment"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8192-5803","authenticated-orcid":false,"given":"Rute Lu\u00edsa","family":"Cabrita Pinto","sequence":"first","affiliation":[{"name":"Laboratory of Human Genetics, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Fancellu","sequence":"additional","affiliation":[{"name":"Unit of Neurology, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Policlinico San Martino, 16132 Genoa, Italy"},{"name":"Clinical Center for Diagnosis of Orphan Patients, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana Benzi","family":"Markushi","sequence":"additional","affiliation":[{"name":"Unit of Neurology, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Policlinico San Martino, 16132 Genoa, Italy"},{"name":"Clinical Center for Diagnosis of Orphan Patients, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3732-9462","authenticated-orcid":false,"given":"Silvia","family":"Viaggi","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3516-2379","authenticated-orcid":false,"given":"Barbara","family":"Testa","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4301-3576","authenticated-orcid":false,"given":"Giuseppina","family":"Conteduca","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lane","family":"Fitzsimmons","sequence":"additional","affiliation":[{"name":"Renaissance School of Medicine, Stony Brook University, 101 Nicolls Road, Stony Brook, NY 11794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8440-865X","authenticated-orcid":false,"given":"Domenico","family":"Coviello","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7669-5270","authenticated-orcid":false,"given":"Angela Elvira","family":"Covone","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.ajhg.2015.01.003","article-title":"De Novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay","volume":"96","author":"Chong","year":"2015","journal-title":"Am. 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