{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T02:17:03Z","timestamp":1789265823168,"version":"build-2803163510"},"reference-count":38,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,5,16]],"date-time":"2022-05-16T00:00:00Z","timestamp":1652659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health","award":["CCR-2017-23669081"],"award-info":[{"award-number":["CCR-2017-23669081"]}]},{"name":"Italian Ministry of Health","award":["RCR-2020-23670068_001"],"award-info":[{"award-number":["RCR-2020-23670068_001"]}]},{"name":"Italian Ministry of Health","award":["RF-2018-12366931"],"award-info":[{"award-number":["RF-2018-12366931"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Objective: The co-occurrence of pathogenic variants has emerged as a relatively common finding underlying complex phenotypes. Here, we used whole-exome sequencing (WES) to solve an unclassified multisystem clinical presentation. Patients and Methods: A 20-year-old woman affected by moderate intellectual disability (ID), dysmorphic features, hypertrichosis, scoliosis, recurrent bronchitis, and pneumonia with bronchiectasis, colelithiasis, chronic severe constipation, and a family history suggestive of autosomal dominant recurrence of polycystic kidney disease was analyzed by WES to identify the genomic events underlying the condition. Results: Four co-occurring genomic events fully explaining the proband\u2019s clinical features were identified. A de novo truncating USP7 variant was disclosed as the cause of Hao\u2013Fountain syndrome, a disorder characterized by syndromic ID and distinctive behavior. Compound heterozygosity for a major cystic fibrosis-causing variant and the modulator allele, IVS8-5T, in CFTR explained the recurrent upper and lower respiratory way infections, bronchiectasis, cholelithiasis, and chronic constipation. Finally, a truncating PKD2 variant co-segregating with polycystic kidney disease in the family allowed presymptomatic disease diagnosis. Conclusions: The co-occurring variants in USP7 and CFTR variants explained the multisystem disorder of the patient. The comprehensive dissection of the phenotype and early diagnosis of autosomal dominant polycystic kidney disease allowed us to manage the CFTR-related disorder symptoms and monitor renal function and other complications associated with PKD2 haploinsufficiency, addressing proper care and surveillance.<\/jats:p>","DOI":"10.3390\/genes13050889","type":"journal-article","created":{"date-parts":[[2022,5,16]],"date-time":"2022-05-16T13:06:23Z","timestamp":1652706383000},"page":"889","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Complex Presentation of Hao-Fountain Syndrome Solved by Exome Sequencing Highlighting Co-Occurring Genomic Variants"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4815-9550","authenticated-orcid":false,"given":"Manuela","family":"Priolo","sequence":"first","affiliation":[{"name":"Unit\u00e0 di Genetica Medica, Grande Ospedale Metropolitano \u201cBianchi-Melacrino-Morelli\u201d, 89124 Reggio Calabria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Mancini","sequence":"additional","affiliation":[{"name":"Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Pizzi","sequence":"additional","affiliation":[{"name":"Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Chiriatti","sequence":"additional","affiliation":[{"name":"Unit\u00e0 di Genetica Medica, Grande Ospedale Metropolitano \u201cBianchi-Melacrino-Morelli\u201d, 89124 Reggio Calabria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1993-8018","authenticated-orcid":false,"given":"Francesca Clementina","family":"Radio","sequence":"additional","affiliation":[{"name":"Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviana","family":"Cordeddu","sequence":"additional","affiliation":[{"name":"Dipartimento di Oncologia e Medicina Molecolare, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Letizia","family":"Pintomalli","sequence":"additional","affiliation":[{"name":"Unit\u00e0 di Genetica Medica, Grande Ospedale Metropolitano \u201cBianchi-Melacrino-Morelli\u201d, 89124 Reggio Calabria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corrado","family":"Mamm\u00ec","sequence":"additional","affiliation":[{"name":"Unit\u00e0 di Genetica Medica, Grande Ospedale Metropolitano \u201cBianchi-Melacrino-Morelli\u201d, 89124 Reggio Calabria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Dallapiccola","sequence":"additional","affiliation":[{"name":"Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7736-9672","authenticated-orcid":false,"given":"Marco","family":"Tartaglia","sequence":"additional","affiliation":[{"name":"Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1056\/NEJMoa1516767","article-title":"Resolution of disease phenotypes resulting from multilocus genomic variation","volume":"376","author":"Posey","year":"2017","journal-title":"N. 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