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Pathogenic <jats:italic>MBTPS2<\/jats:italic> variants also cause BRESHECK syndrome, characterized by the IFAP triad plus intellectual disability and multiple congenital anomalies. Here we present a patient with ichthyosis, sparse hair, pulmonic stenosis, kidney dysplasia, hypospadias, growth failure, thrombocytopenia, anemia, bone marrow fibrosis, and chronic diarrhea found by research\u2010based exome sequencing to harbor a novel, maternally inherited <jats:italic>MBTPS2<\/jats:italic> missense variant (c.766\u2009G&gt;A; (p.Val256Leu)). In vitro modeling supports variant pathogenicity, with impaired cell growth in cholesterol\u2010depleted media, attenuated activation of the sterol regulatory element\u2010binding protein pathway, and failure to activate the endoplasmic reticulum stress response pathway. Our case expands both the genetic and phenotypic spectrum of BRESHECK syndrome to include a novel <jats:italic>MBTPS2<\/jats:italic> variant and cytopenias, bone marrow fibrosis, and chronic diarrhea.<\/jats:p>","DOI":"10.1002\/ajmg.a.62537","type":"journal-article","created":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T19:33:35Z","timestamp":1634758415000},"page":"463-472","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A novel <scp><i>MBTPS2<\/i><\/scp> variant associated with <scp>BRESHECK<\/scp> syndrome impairs <scp>sterol\u2010regulated<\/scp> transcription and the endoplasmic reticulum stress response"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9261-244X","authenticated-orcid":false,"given":"Alanna","family":"Strong","sequence":"first","affiliation":[{"name":"Division of Human Genetics Children's Hospital of Philadelphia  Philadelphia Pennsylvania 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