Skip to main content
SpringerLink
Log in

Single-nucleotide and copy-number variance related to severity of hypospadias

  • Original Article
  • Published:
Pediatric Surgery International Aims and scope Submit manuscript

Abstract

Background

The genetic association of hypospadias-risk studies has been conducted in Caucasians, Chinese-Han populations and few in Indian populations. However, no comprehensive approach has been followed to assess genetic involvement in the severity of the disorder.

Methods

The study evaluated to establish the correlation between genotyped single nucleotide and copy number variants (SNPs/CNVs) and severity of hypospadias by an association in a total 30 SNPs in genes related to sex hormone-biosynthesis and metabolism; embryonic-development and phospholipase-d-signalling pathways on 138 surgery-confirmed hypospadias-cases from North India (84 penile and 28 cases of penoscrotal-hypospadias as compared with 31 cases of glanular + coronal), and analyzed and identified CNVs in four familial cases (18 members) and three paired-sporadic cases (6 members) using array-based comparative-genomic-hybridization and validated in 32 hypospadias samples by TaqMan assay.

Results

Based on odds ratio at 95% CI, Z Statistic and Significance Levels, STS gene-rs17268974 was associated with Penile-Hypospadias and 9-SNPs [seven-SNPs (rs5934740; rs5934842; rs5934913; rs6639811; rs3923341; rs17268974; rs5934937)] of STS gene; rs7562326-SRD5A2 and rs1877031-STARD3 were associated with penoscrotal-hypospadias. On aggregate analysis with p < 0.001, we identified homozygous-loss of Ch7:q34 (PRSS3P2, PRSS2). On validation in previously CNV-characterized and new (32 hypospadias cases), we identified PRSS3P2-loss in most of the grade 3 and 4 hypospadias. Hence, Grade 1 and 2 (coronal and granular) show no-PRSS3P2-loss and no-association with SNPs in STS; SRD5A2; STARD3-gene but Grade 3 and 4 (Penile and Penoscrotal) show PRSS3P2-loss accompanied with the association of SNPs in STS; SRD5A2; STARD3.

Conclusions

Hence, homozygous-loss of PRSS3P2 accompanied with the association of STS; SRD5A2; STARD3 may link to the severity of the disease.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Klip H, Verloop J, van Gool JD et al (2002) Hypospadias in sons of women exposed to diethylstilbestrol in utero: a cohort study. Lancet 359:1102–1107

    Article  PubMed  CAS  Google Scholar 

  2. Harrison SM, Campbell IM, Keays M et al (2013) Screening and familial characterization of copy-number variations in NR5A1 in 46,XY disorders of sex development and premature ovarian failure. Am J Med Genet Part A 161A:2487–2494

    PubMed  Google Scholar 

  3. de la Chapelle A (1987) The Y-chromosomal and autosomal testis-determining genes. Development 101:33–38

    PubMed  Google Scholar 

  4. Liu Y, Ye W, Wu M et al (2017) Association of MAMLD1 single-nucleotide polymorphisms with hypospadias in Chinese Han population. Front Biosci 22:1173–1176

    Article  CAS  Google Scholar 

  5. Samtani R, Bajpai M, Vashisht K et al (2011) Hypospadias risk and polymorphism in SRD5A2 and CYP17 genes: case-control study among Indian children. J Urol 185:2334–2339

    Article  PubMed  CAS  Google Scholar 

  6. Samtani R, Bajpai M, Ghosh PK et al (2015) A49T, R227Q and TA repeat polymorphism of steroid 5 alpha-reductase type II gene and Hypospadias risk in North Indian children. Meta gene 3:1–7

    Article  PubMed  Google Scholar 

  7. Ratan SK, Sharma A, Kapoor S et al (2016) Polymorphism of 3′ UTR of MAMLD1 gene is also associated with increased risk of isolated hypospadias in Indian children: a preliminary report. Pediatr Surg Int 32:515–524

    Article  PubMed  Google Scholar 

  8. Samtani R, Bajpai M, Ghosh PK et al (2010) SRD5A2 gene mutations—a population-based review. Pediatr Endocrinol Rev 8:34–40

    PubMed  Google Scholar 

  9. Qin XY, Kojima Y, Mizuno K et al (2012) Association of variants in genes involved in environmental chemical metabolism and risk of cryptorchidism and hypospadias. J Hum Genet 57:434–441

    Article  PubMed  CAS  Google Scholar 

  10. Codner E, Okuma C, Iniguez G et al (2004) Molecular study of the 3 beta-hydroxysteroid dehydrogenase gene type II in patients with hypospadias. J Clin Endocrinol Metabol 89:957–964

    Article  CAS  Google Scholar 

  11. Sata F, Kurahashi N, Ban S et al (2010) Genetic polymorphisms of 17 beta-hydroxysteroid dehydrogenase 3 and the risk of hypospadias. J Sex Med 7:2729–2738

    Article  PubMed  CAS  Google Scholar 

  12. Kurahashi N, Sata F, Kasai S et al (2005) Maternal genetic polymorphisms in CYP1A1, GSTM1 and GSTT1 and the risk of hypospadias. Mol Hum Reprod 11:93–98

    Article  PubMed  CAS  Google Scholar 

  13. Huang G, Shan W, Zeng L et al (2015) Androgen receptor gene CAG repeat polymorphism and risk of isolated hypospadias: results from a meta-analysis. Genet Mol Res 14:1580–1588

    Article  PubMed  CAS  Google Scholar 

  14. Harada M, Omori A, Nakahara C et al (2015) Tissue-specific roles of FGF signaling in external genitalia development. Dev Dyn 244:759–773

    Article  PubMed  Google Scholar 

  15. Geller F, Feenstra B, Carstensen L et al (2014) Genome-wide association analyses identify variants in developmental genes associated with hypospadias. Nat Genet 46:957–963

    Article  PubMed  CAS  Google Scholar 

  16. Carmichael SL, Witte JS, Ma C et al (2014) Hypospadias and variants in genes related to sex hormone biosynthesis and metabolism. Andrology 2:130–137

    Article  PubMed  CAS  Google Scholar 

  17. Makridakis NM, di Salle E, Reichardt JK (2000) Biochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase type II. Pharmacogenetics 10:407–413

    Article  PubMed  CAS  Google Scholar 

  18. Thai HT, Kalbasi M, Lagerstedt K et al (2005) The valine allele of the V89L polymorphism in the 5-alpha-reductase gene confers a reduced risk for hypospadias. J Clin Endocrinol Metabol 90:6695–6698

    Article  CAS  Google Scholar 

  19. van der Zanden LF, van Rooij IA, Feitz WF et al (2010) Genetics of hypospadias: are single-nucleotide polymorphisms in SRD5A2, ESR1, ESR2, and ATF3 really associated with the malformation? J Clin Endocrinol Metabol 95:2384–2390

    Article  CAS  Google Scholar 

  20. Coughlin CR 2nd, Scharer GH, Shaikh TH (2012) Clinical impact of copy number variation analysis using high-resolution microarray technologies: advantages, limitations and concerns. Genome Med 4:80

    Article  PubMed  PubMed Central  Google Scholar 

  21. Shaikh TH, Kurahashi H, Saitta SC et al (2000) Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum Mol Genet 9:489–501

    Article  PubMed  CAS  Google Scholar 

  22. Shaikh TH, O’Connor RJ, Pierpont ME et al (2007) Low copy repeats mediate distal chromosome 22q11.2 deletions: sequence analysis predicts breakpoint mechanisms. Genome Res 17:482–491

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. van Binsbergen E (2011) Origins and breakpoint analyses of copy number variations: up close and personal. Cytogenet Genome Res 135:271–276

    Article  PubMed  Google Scholar 

  24. Korbel JO, Urban AE, Affourtit JP et al (2007) Paired-end mapping reveals extensive structural variation in the human genome. Science 318:420–426

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Pink RC, Wicks K, Caley DP et al (2011) Pseudogenes: pseudo-functional or key regulators in health disease? RNA 17:792–798

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Dr. Paras Yadav, Senior Application Scientist Imperial Life Sciences for technical assistance. Previously, the abstract has been submitted to “European Paediatric Surgeons’ Association-15th Congress Dublin, Ireland-2014”.

Funding

This study was funded by University Grant from King George Medical University, Lucknow, India.

Author information

Author notes

  1. Neetu Singh and Devendra Kumar Gupta contributed equally.

Authors and Affiliations

  1. Molecular Biology Unit (Center for Advance Research), King George’s Medical University, Lucknow, Uttar Pradesh, 226 003, India

    Neetu Singh, Dinesh Kumar Sahu & Archana Mishra

  2. Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, 110029, India

    Devendra Kumar Gupta, Shilpa Sharma & Devendra Kumar Yadav

  3. Department of Pediatric Surgery, King George’s Medical University, Lucknow, 226 003, India

    Jiledar Rawat

  4. Department of Plastic Surgery, King George’s Medical University, Lucknow, 226 003, India

    Arun Kumar Singh

Authors
  1. Neetu Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Devendra Kumar Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shilpa Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dinesh Kumar Sahu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Archana Mishra
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Devendra Kumar Yadav
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jiledar Rawat
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Arun Kumar Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Neetu Singh or Devendra Kumar Gupta.

Ethics declarations

Conflict of interest

All Authors declares that he/she has no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of Institutional Review Board of the King George Medical University (Lucknow, India).

Informed consent

Informed consent was obtained from all individual participants included in the study for blood collection as well as for the release of all medical records.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Singh, N., Gupta, D.K., Sharma, S. et al. Single-nucleotide and copy-number variance related to severity of hypospadias. Pediatr Surg Int 34, 991–1008 (2018). https://doi.org/10.1007/s00383-018-4330-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00383-018-4330-5

Keywords

Search

Navigation