{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T16:29:08Z","timestamp":1771259348738,"version":"3.50.1"},"reference-count":26,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T00:00:00Z","timestamp":1737590400000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The use of exome sequencing (ES) has helped in detecting many variants and genes that cause primary adrenal insufficiency (PAI). The diagnosis of PAI is difficult and can be life\u2010threatening if not treated urgently. Consanguinity can impact the detection of recessively inherited genes. Here, we report families with PAI in a consanguineous population of Saudi Arabia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>A cohort of 47 PAI patients (41 males and six females) representing 30 families was recruited. The cohort excluded congenital adrenal hyperplasia (CAH) cases and had a known consanguinity of 70%. Using ES, molecular genetic causes of PAI were investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In 30 unrelated families with PAI, pathogenic\/likely pathogenic variants were detected in 27 families with a diagnostic yield of (90%). Clinically associated variants of uncertain significance (VUS) were identified in a further two PAI families (7%). Hemizygous variants in <jats:italic>ABCD1<\/jats:italic> were the most common cause of PAI in this cohort (16 families) leading to adrenoleukodystrophy. A total of six novel variants were detected, of which four were predicted to be pathogenic (P) \/ likely pathogenic (LP) and two were VUS. Four pathogenic variants in <jats:italic>ABCD1<\/jats:italic>, <jats:italic>NR0B1<\/jats:italic>, and <jats:italic>MC2R<\/jats:italic> were detected in 10 families suggesting founder mutations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In this cohort, ES detected a diagnostic molecular abnormality in 90% of patients with PAI phenotypes. X\u2010linked inheritance is the most common cause of PAI and founder mutations likely contributed to a high diagnostic yield.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.70052","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T06:52:16Z","timestamp":1737701536000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Genetics of Primary Adrenal Insufficiency Beyond <scp>CAH<\/scp> in Saudi Arabian Population"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7207-6122","authenticated-orcid":false,"given":"Mohamed H.","family":"Al\u2010Hamed","sequence":"first","affiliation":[{"name":"Department of Clinical Genomics, Center for Genomic Medicine King Faisal Specialist Hospital and Research Center  Riyadh Saudi Arabia"},{"name":"College of Medicine, Alfaisal University  Riyadh Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alya","family":"Qari","sequence":"additional","affiliation":[{"name":"College of Medicine, Alfaisal University  Riyadh Saudi Arabia"},{"name":"Department of Medical Genetics, Center for Genomic Medicine King Faisal Specialist Hospital and Research Center  Riyadh Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lamya","family":"Alrayes","sequence":"additional","affiliation":[{"name":"Department of Pediatrics King Faisal Specialist Hospital and Research Center  Riyadh Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammed","family":"Alotaibi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics King Faisal Specialist Hospital and Research Center  Riyadh Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zainab","family":"Al Masseri","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Qatif Central Hospital, Eastern Health Cluster  Dammam Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Afaf","family":"Alotaibi","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics, Center for Genomic Medicine King Faisal Specialist Hospital and Research Center  Riyadh Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdullah","family":"AlAshwal","sequence":"additional","affiliation":[{"name":"College of Medicine, Alfaisal University  Riyadh Saudi Arabia"},{"name":"Department of Pediatrics King Faisal Specialist Hospital and Research Center  Riyadh Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zuhair N.","family":"AlHassnan","sequence":"additional","affiliation":[{"name":"College of Medicine, Alfaisal University  Riyadh Saudi Arabia"},{"name":"Department of Medical Genetics, Center for Genomic Medicine King Faisal Specialist Hospital and Research Center  Riyadh Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1844-4377","authenticated-orcid":false,"given":"Afaf","family":"Alsagheir","sequence":"additional","affiliation":[{"name":"College of Medicine, Alfaisal University  Riyadh Saudi Arabia"},{"name":"Department of Pediatrics King Faisal Specialist Hospital and Research Center  Riyadh Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,1,23]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2019.00359"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/jpc.13469"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-021-02406-9"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1210\/jendso\/bvab117"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-17-0027"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-1710"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/cen.14109"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1210\/jendso\/bvab086"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2020.619041"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2015.00113"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12920-021-01021-x"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0129099"},{"issue":"12","key":"e_1_2_10_14_1","first-page":"1881","article-title":"Regional Variations in the Prevalence of Consanguinity in Saudi Arabia","volume":"28","author":"El\u2010Mouzan M. 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