Predicted Benign and Synonymous Variants in CYP11A1 Cause Primary Adrenal Insufficiency Through Missplicing

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.eCollection. Cited Medium: Internet. NLM ISO Abbr: J Endocr Soc. PubMed Central ID: PMC6316989. Linked References: J Clin Endocrinol Metab. 2001 Aug;86(8):3820-5. (PMID: 11502818); J Clin Endocrinol Metab. 2002 Aug;87(8):3808-13. (PMID: 12161514); Genomics. 2004 Apr;83(4):566-71. (PMID: 15028279); J Clin Endocrinol Metab. 2005 Jan;90(1):538-41. (PMID: 15507506); J Clin Endocrinol Metab. 2006 Aug;91(8):2821-6. (PMID: 16705068); J Clin Endocrinol Metab. 2006 Dec;91(12):4781-4785. (PMID: 16968793); J Clin Endocrinol Metab. 2008 Mar;93(3):696-702. (PMID: 18182448); J Clin Endocrinol Metab. 2009 Mar;94(3):936-9. (PMID: 19116240); Eur J Endocrinol. 2009 Jul;161(1):195-9. (PMID: 19423561); J Clin Endocrinol Metab. 2009 Oct;94(10):3865-71. (PMID: 19773404); Endocr Rev. 2011 Feb;32(1):81-151. (PMID: 21051590); J Clin Endocrinol Metab. 2011 Mar;96(3):792-8. (PMID: 21159840); Drug Metab Dispos. 2011 Sep;39(9):1577-88. (PMID: 21677063); J Clin Endocrinol Metab. 2011 Nov;96(11):E1798-806. (PMID: 21880796); Biochemistry. 2012 Sep 11;51(36):7064-77. (PMID: 22873692); Eur J Endocrinol. 2012 Dec;167(6):881-5. (PMID: 22968487); J Clin Endocrinol Metab. 2013 Feb;98(2):713-20. (PMID: 23337730); Front Endocrinol (Lausanne). 2015 Aug 05;6:113. (PMID: 26300845); J Biol Chem. 2015 Nov 13;290(46):27700-11. (PMID: 26424794); J Clin Endocrinol Metab. 2016 Jan;101(1):284-92. (PMID: 26523528); Eur J Endocrinol. 2016 May;174(5):601-9. (PMID: 26865584); Nat Commun. 2016 May 10;7:11558. (PMID: 27161764); Genetics. 2016 Jun;203(2):635-47. (PMID: 27270698); Mol Cell Endocrinol. 2017 May 15;447:12-22. (PMID: 28232089); Mol Genet Genomic Med. 2017 Nov;5(6):781-787. (PMID: 29178636); Endocrinology. 1993 Feb;132(2):539-45. (PMID: 8425475); DNA Cell Biol. 1993 Jun;12(5):371-9. (PMID: 8517924); J Clin Endocrinol Metab. 1998 Apr;83(4):1399-400. (PMID: 9543177); Arch Biochem Biophys. 1998 May 1;353(1):109-15. (PMID: 9578606). Linking ISSN: 24721972. Subset: PubMed not MEDLINE; Grant Information: G0901980 United Kingdom MRC_ Medical Research Council; R01 GM086596 United States GM NIGMS NIH HHS; United Kingdom Wellcome Trust; MR/K020455/1 United Kingdom MRC_ Medical Research Council; G0801265 United Kingdom MRC_ Medical Research Council Date of Electronic Publication: 2018 Oct 30. ; Original Imprints: Publication: Washington, DC : Endocrine Society, [2017]- <br />