{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T13:39:06Z","timestamp":1758634746943,"version":"3.41.2"},"reference-count":30,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2020,10,13]],"date-time":"2020-10-13T00:00:00Z","timestamp":1602547200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Mutations in the <jats:italic>PHOX2B<\/jats:italic> gene cause congenital central hypoventilation syndrome (CCHS), a rare autonomic nervous system dysfunction disorder characterized by a decreased ventilatory response to hypercapnia. Affected subjects develop alveolar hypoventilation requiring ventilatory support particularly during the non\u2010REM phase of sleep. In more severe cases, hypoventilation may extend into wakefulness. CCHS is associated with disorders characterized by the defective migration\/differentiation of neural crest derivatives, including aganglionic megacolon or milder gastrointestinal phenotypes, such as constipation. Most cases of CCHS are de novo, caused by heterozygosity for polyalanine repeat expansion mutations (PARMs) in exon 3. About 10% of cases are due to heterozygous non\u2010PARM missense, nonsense or frameshift mutations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We describe a three\u2010generation Maltese\u2010Caucasian family with a variable respiratory\/Hirschsprung phenotype, characterized by chronic constipation, three siblings with Hirschsprung disease necessitating surgery, chronic hypoxia, and alveolar hypoventilation requiring non\u2010invasive ventilation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The sequencing of <jats:italic>PHOX2B<\/jats:italic> revealed a novel heterozygous c.241+2delT splice variant in exon 1 that segregates with the CCHS\/Hirschsprung phenotype in the family. The mutation generates a non\u2010functional splice site with a deleterious effect on protein structure and is pathogenic according to ACMG P VS1, PM2, and PP1 criteria.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This report is significant as no <jats:italic>PHOX2B<\/jats:italic> splice\u2010site mutations have been reported. Additionally, it highlights the variability in clinical expression and disease severity of non\u2010PARM mutations.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1528","type":"journal-article","created":{"date-parts":[[2020,10,13]],"date-time":"2020-10-13T09:09:52Z","timestamp":1602580192000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A respiratory\/Hirschsprung phenotype in a three\u2010generation family associated with a novel pathogenic <i>PHOX2B<\/i> splice donor mutation"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7332-874X","authenticated-orcid":false,"given":"Nikolai Paul","family":"Pace","sequence":"first","affiliation":[{"name":"Centre for Molecular Medicine and Biobanking Faculty of Medicine and Surgery University of Malta Msida Malta"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Pace Bardon","sequence":"additional","affiliation":[{"name":"Department of Medicine Mater Dei Hospital Msida Malta"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabella","family":"Borg","sequence":"additional","affiliation":[{"name":"Centre for Molecular Medicine and Biobanking Faculty of Medicine and Surgery University of Malta Msida Malta"},{"name":"Medical Genetics Unit Department of Pathology Mater Dei Hospital Msida Malta"},{"name":"Department of Pathology Faculty of Medicine and Surgery University of Malta Msida Malta"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,10,13]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1130"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/989741"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13353\u2010018\u20100444\u20107"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200605\u2010607CR"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20944"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13633"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200602\u2010305OC"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11325\u2010011\u20100614\u2010x"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38162"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/children4070055"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.2001.4561"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00383\u2010013\u20103361\u20101"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.52.4.563"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20101\u201061779\u2010176\u20105_17"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22101"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2011\u20103844"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.5664\/jcsm.6670"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.23051"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11325\u2010014\u20100996\u20107"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005792-197011000-00003"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1086\/424530"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.9516"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/140.2.368"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.35499"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.24703"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1203\/01.pdr.0000191814.73340.1d"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi401"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20923"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200807\u20101069ST"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.20527"}],"container-title":["Molecular Genetics &amp; 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