{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T14:34:15Z","timestamp":1791988455812,"version":"4.4.0"},"reference-count":97,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T00:00:00Z","timestamp":1733875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Infantile hypotonia with psychomotor retardation and characteristic facies-1 (IHPRF1, MIM#615419) is a rare, birth onset, autosomal recessive disorder caused by homozygous or compound heterozygous truncating variants in <jats:italic>NALCN<\/jats:italic> gene (MIM#611549) resulting in a loss-of-function effect.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We enrolled a new IHPRF1 patients\u2019 cohort in the framework of an international multicentric collaboration study. Using specialized <jats:italic>in silico<\/jats:italic> pathogenicity predictors and <jats:italic>ad hoc<\/jats:italic> structural analyses, we assessed the mechanistic consequences of the deleterious variants retrieved on NALCN structure and function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>To date 38 different <jats:italic>NALCN<\/jats:italic> variants have been retrieved from 33 different families, 26 from unrelated and 22 from related patients. We report on five new IHPRF1 patients from four different families, harboring four newly identified and one previously retrieved variant that exhibited a markedly significant functional impact, thereby compromising the functionality of the protein complex.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>By widening the functional spectrum of biallelic variants affecting the <jats:italic>NALCN<\/jats:italic> gene, this article broadens the IHPRF1 syndrome\u2019s genotype-phenotype correlation and gives new insight into its pathogenic mechanism, diagnosis, and clinical management.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fgene.2024.1477940","type":"journal-article","created":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T06:56:30Z","timestamp":1733900190000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Widening the infantile hypotonia with psychomotor retardation and characteristic Facies-1 Syndrome\u2019s clinical and molecular spectrum through NALCN in-silico structural analysis"],"prefix":"10.3389","volume":"15","author":[{"given":"Davide","family":"Vecchio","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Macchiaiolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela V.","family":"Gonfiantini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo 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