Genetics of Primary Adrenal Insufficiency Beyond CAH in Saudi Arabian Population
ABSTRACT Background 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‐threatening if not treated urgently. Consanguinity can impact the detection of recessively inherited...
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Wiley
2025-01-01
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| Series: | Molecular Genetics & Genomic Medicine |
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| Online Access: | https://doi.org/10.1002/mgg3.70052 |
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| author | Mohamed H. Al‐Hamed Alya Qari Lamya Alrayes Mohammed Alotaibi Zainab Al Masseri Afaf Alotaibi Abdullah AlAshwal Zuhair N. AlHassnan Afaf Alsagheir |
| author_facet | Mohamed H. Al‐Hamed Alya Qari Lamya Alrayes Mohammed Alotaibi Zainab Al Masseri Afaf Alotaibi Abdullah AlAshwal Zuhair N. AlHassnan Afaf Alsagheir |
| author_sort | Mohamed H. Al‐Hamed |
| collection | DOAJ |
| description | ABSTRACT Background 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‐threatening 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. Materials and Methods 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. Results 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 ABCD1 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 ABCD1, NR0B1, and MC2R were detected in 10 families suggesting founder mutations. Conclusion In this cohort, ES detected a diagnostic molecular abnormality in 90% of patients with PAI phenotypes. X‐linked inheritance is the most common cause of PAI and founder mutations likely contributed to a high diagnostic yield. |
| format | Article |
| id | doaj-art-1733863ecbb64152ab28e91d763873f0 |
| institution | Kabale University |
| issn | 2324-9269 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj-art-1733863ecbb64152ab28e91d763873f02025-01-24T08:16:43ZengWileyMolecular Genetics & Genomic Medicine2324-92692025-01-01131n/an/a10.1002/mgg3.70052Genetics of Primary Adrenal Insufficiency Beyond CAH in Saudi Arabian PopulationMohamed H. Al‐Hamed0Alya Qari1Lamya Alrayes2Mohammed Alotaibi3Zainab Al Masseri4Afaf Alotaibi5Abdullah AlAshwal6Zuhair N. AlHassnan7Afaf Alsagheir8Department of Clinical Genomics, Center for Genomic Medicine King Faisal Specialist Hospital and Research Center Riyadh Saudi ArabiaCollege of Medicine, Alfaisal University Riyadh Saudi ArabiaDepartment of Pediatrics King Faisal Specialist Hospital and Research Center Riyadh Saudi ArabiaDepartment of Pediatrics King Faisal Specialist Hospital and Research Center Riyadh Saudi ArabiaDepartment of Pediatrics Qatif Central Hospital, Eastern Health Cluster Dammam Saudi ArabiaDepartment of Clinical Genomics, Center for Genomic Medicine King Faisal Specialist Hospital and Research Center Riyadh Saudi ArabiaCollege of Medicine, Alfaisal University Riyadh Saudi ArabiaCollege of Medicine, Alfaisal University Riyadh Saudi ArabiaCollege of Medicine, Alfaisal University Riyadh Saudi ArabiaABSTRACT Background 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‐threatening 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. Materials and Methods 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. Results 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 ABCD1 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 ABCD1, NR0B1, and MC2R were detected in 10 families suggesting founder mutations. Conclusion In this cohort, ES detected a diagnostic molecular abnormality in 90% of patients with PAI phenotypes. X‐linked inheritance is the most common cause of PAI and founder mutations likely contributed to a high diagnostic yield.https://doi.org/10.1002/mgg3.70052consanguinitydiagnostic yieldexome sequencingprimary adrenal insufficiency |
| spellingShingle | Mohamed H. Al‐Hamed Alya Qari Lamya Alrayes Mohammed Alotaibi Zainab Al Masseri Afaf Alotaibi Abdullah AlAshwal Zuhair N. AlHassnan Afaf Alsagheir Genetics of Primary Adrenal Insufficiency Beyond CAH in Saudi Arabian Population Molecular Genetics & Genomic Medicine consanguinity diagnostic yield exome sequencing primary adrenal insufficiency |
| title | Genetics of Primary Adrenal Insufficiency Beyond CAH in Saudi Arabian Population |
| title_full | Genetics of Primary Adrenal Insufficiency Beyond CAH in Saudi Arabian Population |
| title_fullStr | Genetics of Primary Adrenal Insufficiency Beyond CAH in Saudi Arabian Population |
| title_full_unstemmed | Genetics of Primary Adrenal Insufficiency Beyond CAH in Saudi Arabian Population |
| title_short | Genetics of Primary Adrenal Insufficiency Beyond CAH in Saudi Arabian Population |
| title_sort | genetics of primary adrenal insufficiency beyond cah in saudi arabian population |
| topic | consanguinity diagnostic yield exome sequencing primary adrenal insufficiency |
| url | https://doi.org/10.1002/mgg3.70052 |
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