Dataset Information

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.

SUBMITTER: Maharaj A

PROVIDER: S-EPMC6316989 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Predicted Benign and Synonymous Variants in <i>CYP11A1</i> Cause Primary Adrenal Insufficiency Through Missplicing.

Maharaj Avinaash A Buonocore Federica F Meimaridou Eirini E Ruiz-Babot Gerard G Guasti Leonardo L Peng Hwei-Ming HM Capper Cameron P CP Burgos-Tirado Neikelyn N Prasad Rathi R Hughes Claire R CR Maudhoo Ashwini A Crowne Elizabeth E Cheetham Timothy D TD Brain Caroline E CE Suntharalingham Jenifer P JP Striglioni Niccolò N Yuksel Bilgin B Gurbuz Fatih F Gupta Sangay S Lindsay Robert R Couch Robert R Spoudeas Helen A HA Guran Tulay T Johnson Stephanie S Fowler Dallas J DJ Conwell Louise S LS McInerney-Leo Aideen M AM Drui Delphine D Cariou Bertrand B Lopez-Siguero Juan P JP Harris Mark M Duncan Emma L EL Hindmarsh Peter C PC Auchus Richard J RJ Donaldson Malcolm D MD Achermann John C JC Metherell Louise A LA

Journal of the Endocrine Society 20181030 1

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 <i>CYP11A1</i> in 19 individuals from 13 different families (allele frequency within undiagnosed PAI in our cohort, 0.102 vs 0.00 ...[more]

PMID: 30620006

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Project description:BackgroundPrimary adrenal insufficiency (PAI) is life-threatening, and a definitive aetiological diagnosis is essential for management and prognostication. We conducted this study to investigate the genetic aetiologies of PAI in South China and explore their clinical features.MethodsSeventy children were enrolled in this cross-sectional study. Clinical information was collected, and combined genetic tests were performed according to the children's manifestations. Statistical analysis was performed among the different groups. In silico or in vitro experiments were applied to determine the pathogenicity of novel variants.ResultsAmong the 70 children, 84.3% (59/70) were diagnosed with congenital adrenal hyperplasia (CAH), and 21-hydroxylase deficiency (21-OHD) was genetically confirmed in 91.5% of these cases. Salt wasting (SW), simple virilization (SV), and non-classic (NC) CAH accounted for 66.1% (39/59), 30.5% (18/59), and 3.4% (2/59) of the cases, respectively. The 17-hydroxyprogesterone (17-OHP) and testosterone (TES) levels were significantly higher in children with SW than with SV. The 17-OHP and cortisol levels in female SW patients were significantly higher than those in males. The 17-OHP, cortisol, dehydroepiandrosterone (DHEAS) and TES levels in female SW patients were significantly higher than those in female SV patients. Additionally, 72.7% (8/11) of uncharacterized PAI patients had positive genetic findings. Among all the patients, two novel variants in the CYP21A2 gene (c.833dupT and c.651 + 2T > G) were found. A microdeletion (Xp21.2-21.3) and five novel variants, including 2 in the NR0B1 gene (c.323-324CG > GA and c.1231_1234delCTCA), 2 in the AAAS gene (c.399 + 1G > A and c.250delT) and 1 in the NNT gene (c.2274delT), were detected. The novel variant c.399 + 1G > A in the AAAS gene was further confirmed to lead to exon 4 skipping during mRNA transcription and produce a truncated ALADIN protein.ConclusionsWe found ethnicity-based differences in the CYP21A2 gene variant spectrum among different study populations. Female 21-OHD patients tended to have higher 17-OHP and TES levels, which warrants caution in relation to the effects of virilization. Novel gene variants detected in the CYP21A2, NR0B1, AAAS and NNT genes expanded the genetic spectrum of PAI, however, further improvement of genetic testing tools beyond our protocol are still needed to uncover the complete aetiology of PAI in children.

Dataset Information

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

Publications

Predicted Benign and Synonymous Variants in <i>CYP11A1</i> Cause Primary Adrenal Insufficiency Through Missplicing.

Similar Datasets

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