{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T07:26:27Z","timestamp":1790666787283,"version":"4.1.0"},"reference-count":85,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2019,8,30]],"date-time":"2019-08-30T00:00:00Z","timestamp":1567123200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2020,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Paired Like homeobox 2B (\n                    <jats:italic>PHOX2B<\/jats:italic>\n                    ) is a gene crucial for the differentiation of the neural lineages of the autonomic nervous system (ANS), whose coding mutations cause congenital central hypoventilation syndrome (CCHS). The vast majority of\n                    <jats:italic>PHOX2B<\/jats:italic>\n                    mutations in CCHS is represented by expansions of a polyalanine region in exon 3, collectively defined PARMs (PolyAlanine Repeat Mutations), the minority being frameshift, missense and nonsense mutations, defined as NPARMs (Non\u2010PARMs). While PARMs are nearly exclusively associated with isolated CCHS, most of NPARMs is detected in syndromic CCHS, presenting with neuroblastoma and\/or Hirschsprung disease. More recently, evidence of a complex role of\n                    <jats:italic>PHOX2B<\/jats:italic>\n                    in the pathogenesis of a wider spectrum of ANS disorders has emerged. Indeed, common and hypomorphic\n                    <jats:italic>PHOX2B<\/jats:italic>\n                    variants, including synonymous, polyalanine\u2010contractions, gene deletions may influence the occurrence of either apparent life\u2010threatening event (ALTE), Sudden Infant Death Syndrome (SIDS), neuroblastoma, or isolated HSCR, likely through small effects on\n                    <jats:italic>PHOX2B<\/jats:italic>\n                    expression levels. After an introduction to the role of\n                    <jats:italic>PHOX2B<\/jats:italic>\n                    in the ANS development, causative mutations, common variants, and gene expression deregulation of the\n                    <jats:italic>PHOX2B<\/jats:italic>\n                    gene are discussed, though the involvement of synonymous variants and contractions requires further confirmations with respect to ANS disorders and molecular mechanisms underlying the\n                    <jats:italic>PHOX2B<\/jats:italic>\n                    phenotypic heterogeneity.\n                  <\/jats:p>","DOI":"10.1111\/cge.13633","type":"journal-article","created":{"date-parts":[[2019,8,24]],"date-time":"2019-08-24T01:23:33Z","timestamp":1566609813000},"page":"103-113","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Causative and common\n                    <i>PHOX2B<\/i>\n                    variants define a broad phenotypic spectrum"],"prefix":"10.1111","volume":"97","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9456-8945","authenticated-orcid":false,"given":"Tiziana","family":"Bachetti","sequence":"first","affiliation":[{"name":"Laboratorio Neurobiologia dello Sviluppo, Dipartimento di Scienze della Terra dell'Ambiente e della Vita (DISTAV) Universit\u00e0 di Genova  Genova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8732-1955","authenticated-orcid":false,"given":"Isabella","family":"Ceccherini","sequence":"additional","affiliation":[{"name":"U.O.C. 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