{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T08:00:57Z","timestamp":1783065657892,"version":"3.54.6"},"reference-count":34,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2011,8,9]],"date-time":"2011-08-09T00:00:00Z","timestamp":1312848000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Chicago Community Trust Foundation PHOX2B Patent Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pediatric Pulmonology"],"published-print":{"date-parts":[[2012,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Clinical testing for <jats:italic>PHOX2B<\/jats:italic> mutations is widely used for patients with any symptoms suggestive of hypoventilation (with\/without anatomic\/physiologic autonomic dysregulation), though not necessarily with the congenital central hypoventilation syndrome (CCHS) phenotype. Consequently, a multitude of referrals for clinical <jats:italic>PHOX2B<\/jats:italic> testing (fragment analysis of the 20 polyalanine repeat region and\/or sequencing of entire coding region) have no identifiable mutation. Whole gene deletions\/duplications have recently been identified as a common disease\u2010causing mechanism, but have not been reported in a clinical population referred for <jats:italic>PHOX2B<\/jats:italic> testing. The objective of this study was to determine if <jats:italic>PHOX2B<\/jats:italic> exon or whole gene deletion\/duplication would be identified in a subset of patients referred for <jats:italic>PHOX2B<\/jats:italic> testing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Hypothesis<\/jats:title><jats:p>We hypothesized that <jats:italic>PHOX2B<\/jats:italic> exon or whole gene deletion or duplication would be identified in a subset of cases who were referred for genetic testing but not found to have a <jats:italic>PHOX2B<\/jats:italic> mutation with currently available clinical <jats:italic>PHOX2B<\/jats:italic> testing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Genomic DNA samples from patients that tested negative for <jats:italic>PHOX2B<\/jats:italic> mutations using fragment analysis and\/or sequencing, and control samples, were screened for <jats:italic>PHOX2B<\/jats:italic> exon deletions\/duplications by multiplex ligation\u2010dependent probe amplification with confirmation by array comparative genomic hybridization.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Deletions of\/in <jats:italic>PHOX2B<\/jats:italic> were identified in 4\/250 patients and 0\/261 controls. The deletions ranged from 6,216 base pairs (involving only <jats:italic>PHOX2B<\/jats:italic> exon 3) to 2.6 megabases (involving all of <jats:italic>PHOX2B<\/jats:italic> and 12 other genes). The case with <jats:italic>PHOX2B<\/jats:italic> partial exon 3 deletion had a CCHS\u2010compatible phenotype (hypoventilation, Hirschsprung disease). Phenotypes for the other three cases, all <jats:italic>PHOX2B<\/jats:italic> whole\u2010gene deletions, were varied including: (1) apparent life threatening event, (2) full CCHS necessitating artificial ventilation with ganglioneuroblastoma, and (3) hypoventilation during sleep. Family studies of two of the four probands showed these deletions to be maternally inherited; the mothers also had phenotypic findings of autonomic dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p><jats:italic>PHOX2B<\/jats:italic> exon or whole gene deletion should be considered as another mechanism of disease which may include CCHS, Hirschsprung disease, and\/or tumors of neural crest origin, although the genotype\u2013phenotype relationship requires further clarification. Pediatr Pulmonol. 2012; 47:153\u2013161. \u00a9 2011 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ppul.21527","type":"journal-article","created":{"date-parts":[[2011,8,9]],"date-time":"2011-08-09T19:37:47Z","timestamp":1312918667000},"page":"153-161","source":"Crossref","is-referenced-by-count":54,"title":["Variable human phenotype associated with novel deletions of the <i>PHOX2B<\/i> gene"],"prefix":"10.1002","volume":"47","author":[{"given":"Lawrence J.","family":"Jennings","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Casey M.","family":"Rand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Kravis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth 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