Molecular genetics & genomic medicine · 2025
Genetics of Primary Adrenal Insufficiency Beyond CAH in Saudi Arabian Population.
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Al-Hamed Mohamed H, Qari Alya, Alrayes Lamya, Alotaibi Mohammed, Al Masseri Zainab, Alotaibi Afaf, AlAshwal Abdullah, AlHassnan Zuhair N, Alsagheir Afaf
Аннотация
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.
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.