{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T17:50:20Z","timestamp":1782841820783,"version":"3.54.5"},"reference-count":36,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,2,17]],"date-time":"2021-02-17T00:00:00Z","timestamp":1613520000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Protein disulfide isomerase A6 (PDIA6) is an unfolded protein response (UPR)\u2010regulating protein. PDIA6 regulates the UPR sensing proteins, Inositol requiring enzyme 1, and EIF2AK3. Biallelic inactivation of the two genes in mice and humans resulted in embryonic lethality, diabetes, skeletal defects, and renal insufficiency. We recently showed that PDIA6 inactivation in mice caused embryonic and early lethality, diabetes and immunodeficiency. Here, we present a case with asphyxiating thoracic dystrophy (ATD) syndrome and infantile\u2010onset diabetes. Whole exome sequencing revealed a homozygous frameshift variant in the <jats:italic>PDIA6<\/jats:italic> gene. RNA expression was reduced in a gene dosage\u2010dependent manner, supporting a loss\u2010of\u2010function effect of this variant. Phenotypic correlation with the mouse model recapitulated the growth defect and delay, early lethality, coagulation, diabetes, immunological, and polycystic kidney disease phenotypes. In general, the phenotype of the current patient is consistent with phenotypes associated with the disruption of PDIA6 and the sensors of UPR in mice and humans. This is the first study to associate ATD to the UPR gene, <jats:italic>PDIA6<\/jats:italic>. We recommend screening ATD cases with or without insulin\u2010dependent diabetes for variants in <jats:italic>PDIA6<\/jats:italic>.<\/jats:p>","DOI":"10.1111\/cge.13930","type":"journal-article","created":{"date-parts":[[2021,1,26]],"date-time":"2021-01-26T08:49:34Z","timestamp":1611650974000},"page":"694-703","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Biallelic loss of function variant in the unfolded protein response gene <i>PDIA6<\/i> is associated with asphyxiating thoracic dystrophy and <scp>neonatal\u2010onset<\/scp> diabetes"],"prefix":"10.1111","volume":"99","author":[{"given":"Fatima M.","family":"Al\u2010Fadhli","sequence":"first","affiliation":[{"name":"Unit of Genetic Diseases, Department of Pediatrics Maternity and Children's Hospital  Almadinah Almunwarah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manal","family":"Afqi","sequence":"additional","affiliation":[{"name":"Unit of Genetic Diseases, Department of Pediatrics Maternity and Children's Hospital  Almadinah Almunwarah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona Hamza","family":"Sairafi","sequence":"additional","affiliation":[{"name":"Department of Nephrology Maternity and Children's Hospital  Almadinah Almunwarah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makki","family":"Almuntashri","sequence":"additional","affiliation":[{"name":"Department of Radiology King Abdulaziz Medical City, King Saud bin Abdulaziz University for Health Sciences  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Essa","family":"Alharby","sequence":"additional","affiliation":[{"name":"Center for Genetics and Inherited Diseases Taibah University  Almadinah Almunwarah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghadeer","family":"Alharbi","sequence":"additional","affiliation":[{"name":"Center for Genetics and Inherited Diseases Taibah University  Almadinah Almunwarah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Firoz","family":"Abdud Samad","sequence":"additional","affiliation":[{"name":"Center for Genetics and Inherited Diseases Taibah University  Almadinah Almunwarah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamil Amjad","family":"Hashmi","sequence":"additional","affiliation":[{"name":"Center for Genetics and Inherited Diseases Taibah University  Almadinah Almunwarah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimah","family":"Zaytuni","sequence":"additional","affiliation":[{"name":"Center for Genetics and Inherited Diseases Taibah University  Almadinah Almunwarah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed A.","family":"Bahashwan","sequence":"additional","affiliation":[{"name":"Laboratory and Blood Bank Department Maternity and Children's Hospital  Almadinah Almunwarah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Huk","family":"Choi","sequence":"additional","affiliation":[{"name":"Center for the Genetics of Host Defense University of Texas Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy W. 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