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Most of the BPS cases reported to date are fatal either in the prenatal or neonatal period. Causative genetic defects of BPS were mapped on the <jats:italic>RIPK4<\/jats:italic> gene encoding receptor\u2010interacting serine\/threonine kinase 4, which is critical for epidermal differentiation and development. <jats:italic>RIPK4<\/jats:italic> variants are associated with a wide range of clinical features ranging from milder ectodermal dysplasia to severe BPS. Here, we evaluated a consanguineous Turkish family, who had two pregnancies with severe multiple malformations compatible with BPS phenotype. In order to identify the underlying genetic defect, direct sequencing of the coding region and exon\u2010intron boundaries of <jats:italic>RIPK4<\/jats:italic> was carried out. A homozygous transversion (c.481G&gt;C) that leads to the substitution of a conserved aspartic acid to histidine (p.Asp161His) in the kinase domain of the protein was detected. Pathogenicity predictions, molecular modeling, and cell\u2010based functional assays showed that Asp161 residue is required for the kinase activity of the protein, which indicates that the identified variant is responsible for the severe BPS phenotype in the family.<\/jats:p>","DOI":"10.1002\/ajmg.a.62154","type":"journal-article","created":{"date-parts":[[2021,3,13]],"date-time":"2021-03-13T18:01:56Z","timestamp":1615658516000},"page":"1691-1699","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A novel homozygous <scp><i>RIPK4<\/i><\/scp> variant in a family with severe <scp>Bartsocas\u2010Papas<\/scp> syndrome"],"prefix":"10.1002","volume":"185","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5054-168X","authenticated-orcid":false,"given":"Tuba","family":"Din\u00e7er","sequence":"first","affiliation":[{"name":"Department of Medical Biology, Faculty of Medicine Karadeniz Technical University  Trabzon Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9932-0730","authenticated-orcid":false,"given":"Evren","family":"G\u00fcm\u00fc\u015f","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Faculty of Medicine Mu\u011fla S\u0131tk\u0131 Ko\u00e7man University  Mu\u011fla Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4500-5668","authenticated-orcid":false,"given":"Bayram","family":"Toraman","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Medicine Karadeniz Technical University  Trabzon Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2139-1787","authenticated-orcid":false,"given":"\u0130dris","family":"Er","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Institute of Health Science Karadeniz Technical University  Trabzon Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6714-3343","authenticated-orcid":false,"given":"Gokhan","family":"Yildiz","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Medicine Karadeniz Technical University  Trabzon Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2085-5773","authenticated-orcid":false,"given":"Zafer","family":"Y\u00fcksel","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Bioscientia GmbH  Ingelheim Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1467-2268","authenticated-orcid":false,"given":"Ersan","family":"Kalay","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Medicine Karadeniz Technical University  Trabzon Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,3,13]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/428714"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/1096-8628(20000731)93:3<194::AID-AJMG6>3.0.CO;2-X"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M004771200"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.9.2.222"},{"key":"e_1_2_9_7_1","volume-title":"Discovery studio Modeling environment, release 2017","author":"Biovia D. 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