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Abstract
Primary adrenal insufficiency (PAI) is a potentially life-threatening condition that can present with nonspecific features and can be difficult to diagnose. We undertook next generation sequencing in a cohort of children and young adults with PAI of unknown etiology from around the world and identified a heterozygous missense variant (rs6161, c.940G>A, p.Glu314Lys) in CYP11A1 in 19 individuals from 13 different families (allele frequency within undiagnosed PAI in our cohort, 0.102 vs 0.0026 in the Genome Aggregation Database; P < 0.0001). Seventeen individuals harbored a second heterozygous rare disruptive variant in CYP11A1 and two had very rare synonymous changes in trans (c.990G>A, Thr330 = ; c.1173C>T, Ser391 =). Although p.Glu314Lys is predicted to be benign and showed no loss-of-function in an Escherichia coli assay system, in silico and in vitro studies revealed that the rs6161/c.940G>A variant, plus the c.990G>A and c.1173C>T changes, affected splicing and that p.Glu314Lys produces a nonfunctional protein in mammalian cells. Taken together, these findings show that compound heterozygosity involving a relatively common and predicted “benign” variant in CYP11A1 is a major contributor to PAI of unknown etiology, especially in European populations. These observations have implications for personalized management and demonstrate how variants that might be overlooked in standard analyses can be pathogenic when combined with other very rare disruptive changes.
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1 Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
2 Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
3 Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Department of Pharmacology, University of Michigan, Ann Arbor, Michigan
4 Department of Paediatric Endocrinology and Diabetes, Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom
5 Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
6 Department of Pediatric Endocrinology and Diabetes, Cukurova University, Adana, Turkey
7 Department of Pediatrics, Hull Royal Infirmary, Hull, United Kingdom
8 Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
9 Division of Pediatric Endocrinology, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
10 Department Pediatric Endocrinology and Diabetes, Marmara University, Istanbul, Turkey
11 Lady Cilento Children’s Hospital, Brisbane, Queensland, Australia; University of Queensland, Brisbane, Queensland, Australia
12 Institute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia
13 Department of Endocrinology, l’Institut du Thorax, Centre Hospitalier Universitaire de Nantes, Nantes, France
14 INSERM UMR 1087, CNRS UMR 6291, l'Institut du Thorax, Université de Nantes, Nantes, France
15 Pediatric Endocrinology Unit, Children’s Hospital, Institute of Biomedical Research in Malaga, Málaga, Spain
16 Institute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia; Department of Endocrinology and Diabetes, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia; Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
17 Department of Paediatrics, University College London Hospitals, London, United Kingdom
18 Section of Child Health, Glasgow University School of Medicine, Glasgow, United Kingdom