Reporting a Novel Homozygous Variant in the HSD11B2 Gene: Reclassifying the Variant Using Sherloc Refinement: A Case Report Study
Archives of Medical Laboratory Sciences,
Vol. 8 (2022),
10 January 2022
,
Page 1-5 (e5)
https://doi.org/10.22037/amls.v8.39377
Abstract
Background and Aim: Apparent mineralocorticoid excess (AME) is an autosomal recessive disorder resulting from a deficiency of 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) caused by mutations in the HSD11B2 gene. The mutated gene affects the enzyme activity which results in the rising of cortisol that can be associated with hypokalemia, severe low-renin mineralocorticoid, hypertension, and sodium retention. Few genetic variants, almost 40, have been reported in this gene and more genetic studies are necessary. In this study, we aim to investigate an Iranian patient suspected of being affected by AME.
Methods: A 2.5-year-old girl from consanguineous parents was referred to Ali Asghar Children’s Hospital. She was born prematurely with a birth weight of 2.20 kg. Her chief complaint was fever, failure to thrive, polydipsia and polyuria. The initial diagnosis was cystic fibrosis (CF), but the results of the sweat test were normal. Other differential diagnoses were apparent mineralocorticoid excess syndrome type 2, Liddle syndrome, and Bartter syndrome type2. Biochemical tests performed on the patient’s free urine showed a high ratio, almost 12, of cortisol to cortisone. Whole exome sequencing (WES) was performed to find out the causative gene.
Conclusion: WES showed a novel homozygous variant in the 11βHSD2 gene. According to the American College of Medical Genetics and Genomics (ACMG) guideline, it was a vindicated uncertain significance (VUS), but using Sherloc refinement suggested that this transversion mutation is most likely to be pathogenic.
*Corresponding Author: Marzieh Mojbafan; Email: mojbafan.m@iums.ac.ir; ORCID ID: 0000-0002-9630-3561
Please cite this article as: Hozhabrpour A, Mojbafan M. Reporting a Novel Homozygous Variant in the HSD11B2 Gene: Reclassifying the Variant Using Sherloc Refinement. Arch Med Lab Sci. 2022;8:1-5 (e5). https://doi.org/10.22037/amls.v8.39377
- Apparent mineralocorticoid excess
- hsd11b2 variant
- AME
- Case Report
How to Cite
References
Náray-Fejes-Tóth A, Watlington Co, Fejes-Tóth G. llβ-Hydroxysteroid Dehydrogenase Activity in the Renal Target Cells of Aldosterone. Endocrinology. 1991;129(1):17-21.
He X, Modi Z, Else T. Hereditary causes of primary aldosteronism and other disorders of apparent excess mineralocorticoid activity. Gland Surgery. 2020;9(1):150.
Ferrari P. The role of 11β-hydroxysteroid dehydrogenase type 2 in human hypertension. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2010;1802(12):1178-87.
Albiston AL, Obeyesekere VR, Smith RE, Krozowski ZS. Cloning and tissue distribution of the human 1 lβ-hydroxysteroid dehydrogenase type 2 enzyme. Molecular and cellular endocrinology. 1994;105(2):R11-R7.
Atanasov AG, Ignatova ID, Nashev LG, Dick B, Ferrari P, Frey FJ, et al. Impaired protein stability of 11β-hydroxysteroid dehydrogenase type 2: a novel mechanism of apparent mineralocorticoid excess. Journal of the American Society of Nephrology. 2007;18(4):1262-70.
Yau M, Nimkarn S. Apparent Mineralocorticoid Excess. Genetic Steroid Disorders: Elsevier; 2014. p. 239-45.
New MI, Geller DS, Fallo F, Wilson RC. Monogenic low renin hypertension. Trends in Endocrinology & Metabolism. 2005;16(3):92-7.
Palermo M, Shackleton CH, Mantero F, Stewart PM. Urinary free cortisone and the assessment of 11β‐hydroxysteroid dehydrogenase activity in man. Clinical endocrinology. 1996;45(5):605-11.
Andrews S. Babraham bioinformatics-FastQC a quality control tool for high throughput sequence data. URL: https://www bioinformatics babraham ac uk/projects/fastqc. 2010.
Matvienko M. CLC Genomics Workbench. Plant and Animal Genome Sr Field Application Scientist, CLC Bio, Aarhus, DE. 2015.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in medicine. 2015;17(5):405-23.
Quang D, Chen Y, Xie X. DANN: a deep learning approach for annotating the pathogenicity of genetic variants. Bioinformatics. 2015;31(5):761-3.
Davydov EV, Goode DL, Sirota M, Cooper GM, Sidow A, Batzoglou S. Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS computational biology. 2010;6(12):e1001025.
Cooper GM, Stone EA, Asimenos G, Green ED, Batzoglou S, Sidow A. Distribution and intensity of constraint in mammalian genomic sequence. Genome research. 2005;15(7):901-13.
Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic acids research. 2019;47(D1):D886-D94.
Ng PC, Henikoff S. SIFT: Predicting amino acid changes that affect protein function. Nucleic acids research. 2003;31(13):3812-4.
Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen‐2. Current protocols in human genetics. 2013;76(1):7.20. 1-7.. 41.
Venselaar H, Te Beek TA, Kuipers RK, Hekkelman ML, Vriend G. Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC bioinformatics. 2010;11(1):1-10.
Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nature methods. 2014;11(4):361-2.
Shihab HA, Gough J, Cooper DN, Day IN, Gaunt TR. Predicting the functional consequences of cancer-associated amino acid substitutions. Bioinformatics. 2013;29(12):1504-10.
Wilson R, Krozowski Z, Li K, Obeyesekere V, Razzaghy-Azar M, Harbison M, et al. A mutation in the HSD11B2 gene in a family with apparent mineralocorticoid excess. The Journal of Clinical Endocrinology & Metabolism. 1995;80(7):2263-6.
Wilson RC, Dave-Sharma S, Wei J-Q, Obeyesekere VR, Li K, Ferrari P, et al. A genetic defect resulting in mild low-renin hypertension. Proceedings of the National Academy of Sciences. 1998;95(17):10200-5.
Itan Y, Shang L, Boisson B, Ciancanelli MJ, Markle JG, Martinez-Barricarte R, et al. The mutation significance cutoff: gene-level thresholds for variant predictions. Nature methods. 2016;13(2):109-10.
Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nature genetics. 2014;46(3):310-5.
Limumpornpetch P, Stewart PM. Apparent mineralocorticoid excess. Encyclopedia of endocrine diseases, 2nd edn Academic, Oxford. 2019:638-43.
Yau M, Haider S, Khattab A, Ling C, Mathew M, Zaidi S, et al. Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency. Proceedings of the National Academy of Sciences. 2017;114(52):E11248-E56.
Morineau G, Sulmont V, Salomon R, Fiquet-Kempf B, Jeunemaître X, Nicod J, et al. Apparent mineralocorticoid excess: report of six new cases and extensive personal experience. Journal of the American Society of Nephrology. 2006;17(11):3176-84.
- Abstract Viewed: 224 times
- PDF Downloaded: 105 times