{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T07:01:47Z","timestamp":1776322907272,"version":"3.50.1"},"reference-count":14,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"vor","delay-in-days":2,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["390873048"],"award-info":[{"award-number":["390873048"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Hum Genome Var"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome type I is a rare, X-linked disorder resulting from pathogenic variants in\n                    <jats:italic>MBTPS2<\/jats:italic>\n                    . Here we report a Pakistani IFAP pedigree of three affected individuals harboring the recurrent\n                    <jats:italic>MBTPS2<\/jats:italic>\n                    splice-site variant c.970+5G&gt;A that was reported previously in Chinese and Argentinian families. Haplotype analyses across these three families excluded a founder effect, establishing c.970+5G&gt;A as a recurrent mutational hotspot. In addition, phenotypic severity varied across the families, suggesting additional modifiers.\n                  <\/jats:p>","DOI":"10.1038\/s41439-026-00346-2","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T01:24:54Z","timestamp":1776129894000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Recurrent MBTPS2 variant c.970+5G&gt;A in IFAP syndrome: a mutational hotspot"],"prefix":"10.1038","volume":"13","author":[{"given":"Sheetal","family":"Kumar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sohail","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pietro","family":"Incardona","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"Cesarato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica Ines","family":"Natale","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad Javed","family":"Khan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8723-5483","authenticated-orcid":false,"given":"Laura","family":"Valinotto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kifayat","family":"Ullah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wasim","family":"Ahmad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ines","family":"Irurzun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter M.","family":"Krawitz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5024-3623","authenticated-orcid":false,"given":"Regina C.","family":"Betz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"346_CR1","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1007\/s10142-025-01694-y","volume":"25","author":"H Huang","year":"2025","unstructured":"Huang, H. et al. MBTPS1: a membrane-bound transcription factor protease implicated in the pathogenesis of several skin and skeletal disorders. Funct. Integr. Genomics 25, 178 (2025).","journal-title":"Funct. Integr. Genomics"},{"key":"346_CR2","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1111\/1346-8138.16684","volume":"50","author":"G Chen","year":"2023","unstructured":"Chen, G., Wang, M., Wang, P. & Liang, B. An intronic splice-site variant in MBTPS2 underlies ichthyosis follicularis with atrichia and photophobia syndrome. J. Dermatol. 50, 715\u2013719 (2023).","journal-title":"J. Dermatol."},{"key":"346_CR3","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1111\/pde.14560","volume":"38","author":"I Irurzun","year":"2021","unstructured":"Irurzun, I. et al. Ichthyosis follicularis, atrichia and photophobia (IFAP) and hereditary mucoepithelial dysplasia: two syndromes that share a common clinical spectrum. Pediatr. Dermatol. 38, 568\u2013574 (2021).","journal-title":"Pediatr. Dermatol."},{"key":"346_CR4","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1038\/ng.3571","volume":"48","author":"P-R Loh","year":"2016","unstructured":"Loh, P.-R., Palamara, P. F. & Price, A. L. Fast and accurate long-range phasing in a UK Biobank cohort. Nat. Genet. 48, 811\u2013816 (2016).","journal-title":"Nat. Genet."},{"key":"346_CR5","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/nature15393","volume":"526","author":"A Auton","year":"2015","unstructured":"Auton, A. et al. A global reference for human genetic variation. Nature 526, 68\u201374 (2015).","journal-title":"Nature"},{"key":"346_CR6","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1016\/j.tig.2020.10.003","volume":"37","author":"AV Nesta","year":"2021","unstructured":"Nesta, A. V., Tafur, D. & Beck, C. R. Hotspots of human mutation. Trends Genet. 37, 717\u2013729 (2021).","journal-title":"Trends Genet."},{"key":"346_CR7","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1038\/s44320-023-00001-w","volume":"20","author":"C Arnedo-Pac","year":"2024","unstructured":"Arnedo-Pac, C., Muinos, F., Gonzalez-Perez, A. & Lopez-Bigas, N. Hotspot propensity across mutational processes. Mol. Syst. Biol. 20, 6\u201327 (2024).","journal-title":"Mol. Syst. Biol."},{"key":"346_CR8","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.dnarep.2017.09.007","volume":"59","author":"E Markkanen","year":"2017","unstructured":"Markkanen, E. Not breathing is not an option: How to deal with oxidative DNA damage. DNA Repair 59, 82\u2013105 (2017).","journal-title":"DNA Repair"},{"key":"346_CR9","doi-asserted-by":"publisher","first-page":"4831","DOI":"10.1093\/nar\/gkab176","volume":"49","author":"LJ Bainbridge","year":"2021","unstructured":"Bainbridge, L. J., Teague, R. & Doherty, A. J. Repriming DNA synthesis: an intrinsic restart pathway that maintains efficient genome replication. Nucleic Acids Res. 49, 4831\u20134847 (2021).","journal-title":"Nucleic Acids Res."},{"key":"346_CR10","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1038\/jhg.2010.163","volume":"56","author":"J Nakayama","year":"2011","unstructured":"Nakayama, J. et al. A Japanese case of ichthyosis follicularis with atrichia and photophobia syndrome with an MBTPS2 mutation. J. Hum. Genet. 56, 250\u2013252 (2011).","journal-title":"J. Hum. Genet."},{"key":"346_CR11","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.ajhg.2020.05.006","volume":"107","author":"H Wang","year":"2020","unstructured":"Wang, H. et al. Mutations in SREBF1, encoding sterol regulatory element binding transcription factor 1, cause autosomal-dominant IFAP syndrome. Am. J. Hum. Genet. 107, 34\u201345 (2020).","journal-title":"Am. J. Hum. Genet."},{"key":"346_CR12","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1016\/j.jaad.2010.02.045","volume":"64","author":"L Tang","year":"2011","unstructured":"Tang, L., Liang, J., Wang, W., Yu, L. & Yao, Z. A novel mutation in MBTPS2 causes a broad phenotypic spectrum of ichthyosis follicularis, atrichia, and photophobia syndrome in a large Chinese family. J. Am. Acad. Dermatol. 64, 716\u2013722 (2011).","journal-title":"J. Am. Acad. Dermatol."},{"key":"346_CR13","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1016\/j.ajhg.2009.03.014","volume":"84","author":"F Oeffner","year":"2009","unstructured":"Oeffner, F. et al. IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response. Am. J. Hum. Genet. 84, 459\u2013467 (2009).","journal-title":"Am. J. Hum. Genet."},{"key":"346_CR14","first-page":"587","volume":"34","author":"D Bornholdt","year":"2013","unstructured":"Bornholdt, D. et al. Genotype\u2013phenotype correlations emerging from the identification of missense mutations in MBTPS2. Hum. Mutat. 34, 587\u2013594 (2013).","journal-title":"Hum. Mutat."}],"container-title":["Human Genome Variation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41439-026-00346-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41439-026-00346-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41439-026-00346-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T06:36:22Z","timestamp":1776321382000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41439-026-00346-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,14]]},"references-count":14,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["346"],"URL":"https:\/\/doi.org\/10.1038\/s41439-026-00346-2","relation":{},"ISSN":["2054-345X"],"issn-type":[{"value":"2054-345X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,14]]},"assertion":[{"value":"31 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 January 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 March 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 April 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Ethical approval was granted by the ethics committee of the Institute of Biochemistry, University of Balochistan, Quetta, Pakistan, the ethics committee on human experimentation of Anhui Medical University, and the ethics committee of the Unidad de Dermatolog\u00eda, Hospital de Ni\u00f1os Dr. Ricardo Guti\u00e9rrez, Buenos Aires, Argentina. All patients gave written, informed consent for participation and publication.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"9"}}