Predicted benign and synonymous variants in CYP11A1 cause primary adrenal insufficiency through missplicing
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 identif...
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| Format: | Article |
| Language: | English |
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Endocrine Society
2018
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| Subjects: | |
| Online Access: | https://repository.londonmet.ac.uk/4983/2/CYP11A1%20variants-%20Avi.pdf |
| _version_ | 1804072400897179648 |
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| author | Maharaj, Avinaash Buonocore, Federica Meimaridou, Eirini Ruiz-Babot, Gerard Guasti, Leonardo Peng, Hwei-Ming Capper, Cameron P. Burgos-Tirado, Neikelyn Prasad, Rathi Hughes, Claire R. Maudhoo, Ashwini Crowne, Elizabeth Cheetham, Timothy D. Brain, Caroline E. Suntharalingham, Jenifer P. Striglioni, Niccolò Yuksel, Bilgin Gurbuz, Fatih Gupta, Sangay Lindsay, Robert Couch, Robert Spoudeas, Helen A. Guran, Tulay Johnson, Stephanie Fowler, Dallas J. Conwell, Louise S. McInerney-Leo, Aideen M. Drui, Delphine Cariou, Bertrand Lopez-Siguero, Juan P. Harris, Mark Duncan, Emma L. Hindmarsh, Peter C. Auchus, Richard J. Donaldson, Malcolm D. Achermann, John C. Metherell, Louise A. |
| author_facet | Maharaj, Avinaash Buonocore, Federica Meimaridou, Eirini Ruiz-Babot, Gerard Guasti, Leonardo Peng, Hwei-Ming Capper, Cameron P. Burgos-Tirado, Neikelyn Prasad, Rathi Hughes, Claire R. Maudhoo, Ashwini Crowne, Elizabeth Cheetham, Timothy D. Brain, Caroline E. Suntharalingham, Jenifer P. Striglioni, Niccolò Yuksel, Bilgin Gurbuz, Fatih Gupta, Sangay Lindsay, Robert Couch, Robert Spoudeas, Helen A. Guran, Tulay Johnson, Stephanie Fowler, Dallas J. Conwell, Louise S. McInerney-Leo, Aideen M. Drui, Delphine Cariou, Bertrand Lopez-Siguero, Juan P. Harris, Mark Duncan, Emma L. Hindmarsh, Peter C. Auchus, Richard J. Donaldson, Malcolm D. Achermann, John C. Metherell, Louise A. |
| author_sort | Maharaj, Avinaash |
| collection | LMU |
| description | 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. |
| first_indexed | 2024-07-09T03:58:33Z |
| format | Article |
| id | oai:repository.londonmet.ac.uk:4983 |
| institution | London Metropolitan University |
| language | English |
| last_indexed | 2024-07-09T03:58:33Z |
| publishDate | 2018 |
| publisher | Endocrine Society |
| record_format | eprints |
| spelling | oai:repository.londonmet.ac.uk:49832020-06-04T09:56:08Z http://repository.londonmet.ac.uk/4983/ Predicted benign and synonymous variants in CYP11A1 cause primary adrenal insufficiency through missplicing Maharaj, Avinaash Buonocore, Federica Meimaridou, Eirini Ruiz-Babot, Gerard Guasti, Leonardo Peng, Hwei-Ming Capper, Cameron P. Burgos-Tirado, Neikelyn Prasad, Rathi Hughes, Claire R. Maudhoo, Ashwini Crowne, Elizabeth Cheetham, Timothy D. Brain, Caroline E. Suntharalingham, Jenifer P. Striglioni, Niccolò Yuksel, Bilgin Gurbuz, Fatih Gupta, Sangay Lindsay, Robert Couch, Robert Spoudeas, Helen A. Guran, Tulay Johnson, Stephanie Fowler, Dallas J. Conwell, Louise S. McInerney-Leo, Aideen M. Drui, Delphine Cariou, Bertrand Lopez-Siguero, Juan P. Harris, Mark Duncan, Emma L. Hindmarsh, Peter C. Auchus, Richard J. Donaldson, Malcolm D. Achermann, John C. Metherell, Louise A. 570 Life sciences; biology 610 Medicine & health 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. Endocrine Society 2018-10-30 Article PeerReviewed text en https://repository.londonmet.ac.uk/4983/2/CYP11A1%20variants-%20Avi.pdf Maharaj, Avinaash, Buonocore, Federica, Meimaridou, Eirini, Ruiz-Babot, Gerard, Guasti, Leonardo, Peng, Hwei-Ming, Capper, Cameron P., Burgos-Tirado, Neikelyn, Prasad, Rathi, Hughes, Claire R., Maudhoo, Ashwini, Crowne, Elizabeth, Cheetham, Timothy D., Brain, Caroline E., Suntharalingham, Jenifer P., Striglioni, Niccolò, Yuksel, Bilgin, Gurbuz, Fatih, Gupta, Sangay, Lindsay, Robert, Couch, Robert, Spoudeas, Helen A., Guran, Tulay, Johnson, Stephanie, Fowler, Dallas J., Conwell, Louise S., McInerney-Leo, Aideen M., Drui, Delphine, Cariou, Bertrand, Lopez-Siguero, Juan P., Harris, Mark, Duncan, Emma L., Hindmarsh, Peter C., Auchus, Richard J., Donaldson, Malcolm D., Achermann, John C. and Metherell, Louise A. (2018) Predicted benign and synonymous variants in CYP11A1 cause primary adrenal insufficiency through missplicing. Journal of the Endocrine Society, 3 (1). pp. 201-221. ISSN 2472-1972 http://dx.doi.org/10.1210/js.2018-00130 10.1210/js.2018-00130 |
| spellingShingle | 570 Life sciences; biology 610 Medicine & health Maharaj, Avinaash Buonocore, Federica Meimaridou, Eirini Ruiz-Babot, Gerard Guasti, Leonardo Peng, Hwei-Ming Capper, Cameron P. Burgos-Tirado, Neikelyn Prasad, Rathi Hughes, Claire R. Maudhoo, Ashwini Crowne, Elizabeth Cheetham, Timothy D. Brain, Caroline E. Suntharalingham, Jenifer P. Striglioni, Niccolò Yuksel, Bilgin Gurbuz, Fatih Gupta, Sangay Lindsay, Robert Couch, Robert Spoudeas, Helen A. Guran, Tulay Johnson, Stephanie Fowler, Dallas J. Conwell, Louise S. McInerney-Leo, Aideen M. Drui, Delphine Cariou, Bertrand Lopez-Siguero, Juan P. Harris, Mark Duncan, Emma L. Hindmarsh, Peter C. Auchus, Richard J. Donaldson, Malcolm D. Achermann, John C. Metherell, Louise A. Predicted benign and synonymous variants in CYP11A1 cause primary adrenal insufficiency through missplicing |
| title | Predicted benign and synonymous variants in CYP11A1 cause primary adrenal insufficiency through missplicing |
| title_full | Predicted benign and synonymous variants in CYP11A1 cause primary adrenal insufficiency through missplicing |
| title_fullStr | Predicted benign and synonymous variants in CYP11A1 cause primary adrenal insufficiency through missplicing |
| title_full_unstemmed | Predicted benign and synonymous variants in CYP11A1 cause primary adrenal insufficiency through missplicing |
| title_short | Predicted benign and synonymous variants in CYP11A1 cause primary adrenal insufficiency through missplicing |
| title_sort | predicted benign and synonymous variants in cyp11a1 cause primary adrenal insufficiency through missplicing |
| topic | 570 Life sciences; biology 610 Medicine & health |
| url | https://repository.londonmet.ac.uk/4983/2/CYP11A1%20variants-%20Avi.pdf |
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