Skip to main content
SpringerLink
Log in

A Novel Nonsense Mutation c.374C>G in CYP21A2 Gene of a Vietnamese Patient with Congenital Adrenal Hyperplasia

  • Conference paper
  • First Online:
Cancer Biology and Advances in Treatment

Part of the book series: Advances in Experimental Medicine and Biology ((ICRRM,volume 1292))

Abstract

Inactivating mutations of the CYP21A2 gene, encoding for steroid synthesis, have been reported in patients with congenital adrenal hyperplasia (CAH). We report a case of an infant who were diagnosed with CAH and presented with the severe phenotype of CAH with symptoms such as increased testicular volume, elevated of 17-hydroxyprogesteron, testosterone and progesterone. In this study, we established an assay for the detection of unusual genetic in the CYP21A2 gene in the proband and his family. A novel nonsense mutation c.374C > G which caused a substitutions of Serine for a stop codon at codon 125 (p.S125*) within exon 3 was found in the proband. Parental genotype studies confirmed carrier state in the father, but the mother showed a wild allele by PCR and sequencing. This inspired us to find deletions using multiplex ligation-dependent probe amplification (MLPA) technique. The probands were found to have a large deletion in exons 1 and 3, while the mother only had deletion in exon 1. Therefore, mutation c.374C > G (p.S125*) in the proband is considered as a heterozygous deletion. This mutation caused a truncated protein which lead to the salt wasting CAH phenotype of the proband. This novel nonsense mutation expands the CYP21A2 mutation spectrum in CAH disorder. This case also highlights the need of caution when interpreting results of molecular genetic testing during genetic counseling.

Authors Chi Dung Vu and Thanh Van Ta have been equally contributed to this chapter.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 229.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 299.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 299.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

17-OHP:

17-hydroxyprogesterone

CAH:

Congenital adrenal hyperplasia

MLPA:

Multiplex ligation-dependent probe amplification

NC:

Nonclassical CAH

SV:

Simple virilizing CAH

SW:

Salt-wasting CAH

WT:

Wild-type

References

  • Baradaran-Heravi, A., Vakili, R., Robins, T., Carlsson, J., Ghaemi, N., A’rabi, A., & Abbaszadegan, M. R. (2007). Three novel CYP21A2 mutations and their protein modelling in patients with classical 21-hydroxylase deficiency from northeastern Iran. Clinical Endocrinology, 67(3), 335–341.

    Article  CAS  Google Scholar 

  • Bernal, G. C., Fernández, S. C., Martinez, S., & Ezquieta, Z. B. (2006). Premature androgenetic alopecia in adult male with nonclassic 21-OH deficiency. A novel nonsense CYP21A2 mutation (Y336X) in 2 affected siblings. Medicina Clínica (Barcelona), 127(16), 617–621.

    Article  Google Scholar 

  • Bidet, M., Bellanne-Chantelot, C., Galand-Portier, M. B., Tardy, V., Billaud, L., Laborde, K., Coussieu, C., Morel, Y., Vaury, C., Golmard, J. L., & Claustre, A. (2009). Clinical and molecular characterization of a cohort of 161 unrelated women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency and 330 family members. The Journal of Clinical Endocrinology & Metabolism, 94(5), 1570–1578.

    Article  CAS  Google Scholar 

  • Bongiovanni, A. M., & Root, A. W. (1963). The adrenogenital syndrome. The New England Journal of Medicine, 268, 1283–1289.

    Article  CAS  Google Scholar 

  • Carvalho, D. F., Miranda, M. C., Gomes, L. G., Madureira, G., Marcondes, J. A., Billerbeck, A. E., Rodrigues, A., Presti, P. F., Kuperman, H., Damiani, D., & Mendonca, B. B. (2016). Molecular CYP21A2 diagnosis in 480 Brazilian patients with congenital adrenal hyperplasia before newborn screening introduction. European Journal of Endocrinology, 16, EJE-16.

    Google Scholar 

  • Chamberlain, J. S., Gibbs, R. A., Rainer, J. E., Nguyen, P. N., & Thomas, C. (1988). Deletion screening of the Duchenne muscular dystrophy locus via multiplex DNA amplification. Nucleic Acids Research, 16(23), 11141–11156.

    Article  CAS  Google Scholar 

  • Coeli, F. B., Soardi, F. C., Bernardi, R. D., de Araújo, M., Paulino, L. C., Lau, I. F., Petroli, R. J., de Lemos-Marini, S. H., Baptista, M. T., Guerra-Júnior, G., & de-Mello, M. P. (2010). Novel deletion alleles carrying CYP21A1P/A2 chimeric genes in Brazilian patients with 21-hydroxylase deficiency. BMC Medical Genetics, 11(1), 1.

    Article  Google Scholar 

  • Concolino, P., & Costella, A. (2018). Congenital Adrenal Hyperplasia (CAH) due to 21-Hydroxylase Deficiency: A comprehensive focus on 233 pathogenic variants of CYP21A2 gene. Molecular Diagnosis & Therapy, 15, 1–20.

    Google Scholar 

  • Concolino, P., Mello, E., Toscano, V., Ameglio, F., Zuppi, C., & Capoluongo, E. (2009). Multiplex ligation-dependent probe amplification (MLPA) assay for the detection of CYP21A2 gene deletions/duplications in congenital adrenal hyperplasia: First technical report. Clinica Chimica Acta, 402(1), 164–170.

    Article  CAS  Google Scholar 

  • Di Pasquale, L., Indovina, S., Wasniewska, M., Mirabelli, S., Porcelli, P., Rulli, I., Salzano, G., & De Luca, F. (2007). Novel nonsense mutation (W22X) in CYP21A2 gene causing salt-wasting congenital adrenal hyperplasia in a compound heterozygous girl. Journal of Endocrinological Investigation, 30(9), 806–807.

    Article  Google Scholar 

  • Einaudi, S., Napolitano, E., Restivo, F., Motta, G., Baldi, M., Tuli, G., Grosso, E., Migone, N., Menegatti, E., & Manieri, C. (2011). Genotype, phenotype and hormonal levels correlation in non-classical congenital adrenal hyperplasia. Journal of Endocrinological Investigation, 34(9), 660–664.

    CAS  PubMed  Google Scholar 

  • Ezquieta, B., Cueva, E., Oyarzabal, M., Oliver, A., Varela, J. M., & Jariego, C. (2002). Gene conversion (655G splicing mutation) and the founder effect (Gln318Stop) contribute to the most frequent severe point mutations in congenital adrenal hyperplasia (21-hydroxylase deficiency) in the Spanish population. Clinical Genetics, 62(2), 181–188.

    Article  CAS  Google Scholar 

  • Globerman, H., Amor, M., Parker, K. L., New, M. I., & White, P. C. (1988). Nonsense mutation causing steroid 21-hydroxylase deficiency. The Journal of Clinical Investigation, 82(1), 139.

    Article  CAS  Google Scholar 

  • Haider, S., Islam, B., D’Atri, V., Sgobba, M., Poojari, C., Sun, L., Yuen, T., Zaidi, M., & New, M. I. (2013). Structure–phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia. Proceedings of the National Academy of Sciences of the United States of America, 110(7), 2605–2610.

    Article  CAS  Google Scholar 

  • Jankowski, S., Currie-Fraser, E., Xu, L., & Coffa, J. (2008). Multiplex ligation-dependent probe amplification analysis on capillary electrophoresis instruments for a rapid gene copy number study. Journal of Biomolecular Techniques, 19(4), 238–243.

    PubMed  Google Scholar 

  • Kharrat, M., Tardy, V., M’Rad, R., Maazoul, F., Jemaa, L. B., Refaï, M., Morel, Y., & Chaabouni, H. (2004). Molecular genetic analysis of Tunisian patients with a classic form of 21-hydroxylase deficiency: Identification of four novel mutations and high prevalence of Q318X mutation. The Journal of Clinical Endocrinology and Metabolism, 89(1), 368–374.

    Article  CAS  Google Scholar 

  • Kolahdouz, M., Hashemipour, M., Khanahmad, H., Rabbani, B., Salehi, M., Rabbani, A., Ansari, A., & Naseri, M. M. (2016). Mutation detection of CYP21A2 gene in nonclassical congenital adrenal hyperplasia patients with premature pubarche. Advanced Biomedical Research, 5, 33.

    Article  Google Scholar 

  • Krone, N., Roscher, A. A., Schwarz, H. P., & Braun, A. (1998). Comprehensive analytical strategy for mutation screening in 21-hydroxylase deficiency. Clinical Chemistry, 44(10), 2075–2082.

    Article  CAS  Google Scholar 

  • Krone, N., Rose, I. T., Willis, D. S., Hodson, J., Wild, S. H., Doherty, E. J., Hahner, S., Parajes, S., Stimson, R. H., Han, T. S., & Carroll, P. V. (2013). Genotype-phenotype correlation in 153 adult patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: Analysis of the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) cohort. The Journal of Clinical Endocrinology and Metabolism, 98(2), E346–E354.

    Article  CAS  Google Scholar 

  • Lai, K. K., Lo, I. F., Tong, T. M., Cheng, L. Y., & Lam, S. T. (2006). Detecting exon deletions and duplications of the DMD gene using Multiplex Ligation-dependent Probe Amplification (MLPA). Clinical Biochemistry, 39(4), 367–372.

    Article  CAS  Google Scholar 

  • Lajic, S., & Wedell, A. (1996). An intron 1 splice mutation and a nonsense mutation (W23X) in CYP21 causing severe congenital adrenal hyperplasia. Human Genetics, 98(2), 182–184.

    Article  CAS  Google Scholar 

  • Lee, H. H., Chao, H. T., Lee, Y. J., Shu, S. G., Chao, M. C., Kuo, J. M., & Chung, B. C. (1998). Identification of four novel mutations in the CYP21 gene in congenital adrenal hyperplasia in the Chinese. Human Genetics, 103(3), 304–310.

    Article  CAS  Google Scholar 

  • Levo, A., & Partanen, J. (1997). Novel nonsense mutation (W302X) in the steroid 21-hydroxylase gene of a Finnish patient with the salt-wasting form of congenital adrenal hyperplasia. Human Mutation, 9(4), 363–365.

    Article  CAS  Google Scholar 

  • Loidi, L., Quinteiro, C., Parajes, S., Barreiro, J., Lestón, D. G., Cabezas-Agrícola, J. M., Sueiro, A. M., Araujo-Vilar, D., Catro-Feijóo, L., Costas, J., & Pombo, M. (2006). High variability in CYP21A2 mutated alleles in Spanish 21-hydroxylase deficiency patients, six novel mutations and a founder effect. Clinical Endocrinology, 64(3), 330–336.

    Article  CAS  Google Scholar 

  • Marino, R., Ramirez, P., Galeano, J., Perez Garrido, N., Rocco, C., Ciaccio, M., Warman, D. M., Guercio, G., Chaler, E., Maceiras, M., & Bergadá, I. (2011). Steroid 21-hydroxylase gene mutational spectrum in 454 Argentinean patients: Genotype–phenotype correlation in a large cohort of patients with congenital adrenal hyperplasia. Clinical Endocrinology, 75(4), 427–435.

    Article  CAS  Google Scholar 

  • Marumudi, E., Sharma, A., Kulshreshtha, B., Khadgawat, R., Khurana, M. L., & Ammini, A. C. (2012). Molecular genetic analysis of CYP21A2 gene in patients with congenital adrenal hyperplasia. Indian Journal of Endocrinology and Metabolism, 16(3), 384.

    Article  CAS  Google Scholar 

  • Massimi, A., Malaponti, M., Federici, L., Vinciguerra, D., Bitti, M. M., Vottero, A., Ghizzoni, L., Maccarrone, M., Cappa, M., Bernardini, S., & Porzio, O. (2014). Functional and structural analysis of four novel mutations of CYP21A2 gene in Italian patients with 21-hydroxylase deficiency. Hormone and Metabolic Research, 46(07), 515–520.

    Article  CAS  Google Scholar 

  • Nunez, B. S., Lobato, M. N., White, P. C., & Meseguer, A. (1999). Functional analysis of four CYP21 mutations from Spanish patients with congenital adrenal hyperplasia. Biochemical and Biophysical Research Communications, 262(3), 635–637.

    Article  CAS  Google Scholar 

  • Ohlsson, G., Müller, J., Skakkebæk, N. E., & Schwartz, M. (1999). Steroid 21-hydroxylase deficiency: Mutational spectrum in Denmark, three novel mutations, and in vitro expression analysis. Human Mutation, 13(6), 482–486.

    Article  CAS  Google Scholar 

  • Rabbani, B., Mahdieh, N., Ashtiani, M. T., Larijani, B., Akbari, M. T., New, M., Parsa, A., Schouten, J. P., & Rabbani, A. (2012). Mutation analysis of the CYP21A2 gene in the Iranian population. Genetic Testing and Molecular Biomarkers, 16(2), 82–90.

    Article  CAS  Google Scholar 

  • Simonetti, L., Bruque, C. D., Fernández, C. S., Benavides-Mori, B., Delea, M., Kolomenski, J. E., Espeche, L. D., Buzzalino, N. D., Nadra, A. D., & Dain, L. (2018). CYP21A2 mutation update: Comprehensive analysis of databases and published genetic variants. Human Mutation, 39(1), 5–22.

    Article  CAS  Google Scholar 

  • Speiser, P. W., & White, P. C. (2003). Congenital adrenal hyperplasia. The New England Journal of Medicine, 349(8), 776788.

    Article  Google Scholar 

  • Speiser, P. W., Azziz, R., Baskin, L. S., Ghizzoni, L., Hensle, T. W., Merke, D. P., Meyer-Bahlburg, H. F., Miller, W. L., Montori, V. M., Oberfield, S. E., & Ritzen, M. (2010). Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: An Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology and Metabolism, 95(9), 4133–4160.

    Article  CAS  Google Scholar 

  • Stikkelbroeck, N. M., Hoefsloot, L. H., de Wijs, I. J., Otten, B. J., Hermus, A. R., & Sistermans, E. A. (2003). CYP21 gene mutation analysis in 198 patients with 21-hydroxylase deficiency in The Netherlands: Six novel mutations and a specific cluster of four mutations. The Journal of Clinical Endocrinology and Metabolism, 88(8), 3852–3859.

    Article  CAS  Google Scholar 

  • Vrzalová, Z., Hrubá, Z., St’ahlová Hrabincová, E., Pouchlá, S., Votava, F., Kolousková, S., & Fajkusová, L. (2010). Identification of CYP21A2 mutant alleles in Czech patients with 21-hydroxylase deficiency. International Journal of Molecular Medicine, 26(4), 595.

    PubMed  Google Scholar 

  • Vrzalová, Z., Hrubá, Z., Hrabincová, E. S., Vrábelová, S., Votava, F., Koloušková, S., & Fajkusová, L. (2011). Chimeric CYP21A1P/CYP21A2 genes identified in Czech patients with congenital adrenal hyperplasia. European Journal of Medical Genetics, 54(2), 112–117.

    Article  Google Scholar 

  • Wedell, A., & Luthman, H. (1993). Steroid 21-hydroxylase deficiency: Two additional mutations in salt-wasting disease and rapid screening of disease-causing mutations. Human Molecular Genetics, 2(5), 499–504.

    Article  CAS  Google Scholar 

  • White, P. C., & Speiser, P. W. (2000). Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocrine Reviews, 21(3), 245–291.

    CAS  PubMed  Google Scholar 

  • Xu, Z., Chen, W., Merke, D. P., & McDonnell, N. B. (2013). Comprehensive mutation analysis of the CYP21A2 gene: An efficient multistep approach to the molecular diagnosis of congenital adrenal hyperplasia. The Journal of Molecular Diagnostics, 15(6), 745–753.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank the patients and their families for their voluntary involvement in this study. This work was supported by the Ministry of Health and National Foundation for Science and Technology Development (NAFOSTED) research fund, Vietnam.

Declaration

The study was approved by the Hanoi Medical University’s scientific and ethical committees (IRB00003121, Hanoi Medical University Institutional Review Board, Hanoi, Vietnam). Informed consent of the patient’s family was obtained prior to sample collection and analysis.

Author information

Author notes

    Authors and Affiliations

    1. Center for Gene and Protein Research, Hanoi Medical University, Hanoi, Vietnam

      Chi Dung Vu, Thanh Van Ta, Thinh Huy Tran & Van Khanh Tran

    2. Vietnam National Children Hospital Hanoi, Vietnam, Department of Medical Genetics, Metabolism & Endocrinology, Hanoi, Vietnam

      Chi Dung Vu

    3. Institute of Genome Research, Vietnam Academy of Science and Technology, Hanoi, Vietnam

      Ngoc-Lan Nguyen, Huy-Hoang Nguyen & Thi Kim Lien Nguyen

    Authors
    1. Chi Dung Vu
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Thanh Van Ta
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Ngoc-Lan Nguyen
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Huy-Hoang Nguyen
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Thi Kim Lien Nguyen
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Thinh Huy Tran
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Van Khanh Tran
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Thanh Van Ta .

    Editor information

    Editors and Affiliations

    1. Stem Cell Institute, University of Science, Vietnam National University, Ho Chi Minh, Vietnam

      Phuc Van Pham

    Rights and permissions

    Reprints and permissions

    Copyright information

    © 2018 Springer Nature Switzerland AG

    About this paper

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this paper

    Vu, C.D. et al. (2018). A Novel Nonsense Mutation c.374C>G in CYP21A2 Gene of a Vietnamese Patient with Congenital Adrenal Hyperplasia. In: Pham, P.V. (eds) Cancer Biology and Advances in Treatment. Advances in Experimental Medicine and Biology(), vol 1292. Springer, Cham. https://doi.org/10.1007/5584_2018_300

    Download citation

    Publish with us

    Policies and ethics

    Search

    Navigation