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In this report, we describe a 5-year-old female who presented severe clinical features, including restrictive cardiomyopathy, developmental delay, spasticity and dysmorphic features. Trio-whole-exome sequencing and segregation analysis were performed to identify the genetic cause of the disease within the family. A novel homozygous nonsense variant in the <jats:italic>DCBLD2<\/jats:italic> gene (c.80G\u2009&gt;\u2009A, p.W27*) was identified as the most likely cause of the patient\u2019s phenotype. This nonsense variant falls in the extracellular N-terminus of\u00a0<jats:italic>DCBLD2<\/jats:italic> and thus might affect proper protein function of the transmembrane receptor. A number of in vitro investigations were performed on the proband\u2019s skin fibroblasts compared to normal fibroblasts, which allowed a comprehensive assessment resulting in the functional characterization of the identified <jats:italic>DCBLD2<\/jats:italic> nonsense variant in different cellular processes. Our data propose a significant association between the identified variant and the observed reduction in cell proliferation, cell cycle progression, intracellular ROS, and Ca2\u2009+\u2009levels, which would likely explain the phenotypic presentation of the patient as associated with lethal restrictive cardiomyopathy.<\/jats:p>","DOI":"10.1038\/s41598-021-92026-0","type":"journal-article","created":{"date-parts":[[2021,6,18]],"date-time":"2021-06-18T10:03:33Z","timestamp":1624010613000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["A homozygous nonsense mutation in DCBLD2 is a candidate cause of developmental delay, dysmorphic features and restrictive cardiomyopathy"],"prefix":"10.1038","volume":"11","author":[{"given":"Kheloud M.","family":"Alhamoudi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tlili","family":"Barhoumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamad","family":"Al-Eidi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulaziz","family":"Asiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwan","family":"Nashabat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manal","family":"Alaamery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masheal","family":"Alharbi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yazeid","family":"Alhaidan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brahim","family":"Tabarki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Umair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majid","family":"Alfadhel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,18]]},"reference":[{"key":"92026_CR1","doi-asserted-by":"publisher","first-page":"1807","DOI":"10.1161\/CIRCULATIONAHA.106.174287","volume":"113","author":"BJ Maron","year":"2006","unstructured":"Maron, B. 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