Skip to main content
SpringerLink
Log in

Newborn screening and single nucleotide variation profiling of TSHR, TPO, TG and DUOX2 candidate genes for congenital hypothyroidism

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

High prevalence of congenital hypothyroidism (CH) among Indian newborns prompted us to establish population-specific reference ranges of TSH and to explore the contribution of the common genetic variants in TSHR, TPO, TG and DUOX2 genes towards CH. A total of 1144 newborns (593 males and 551 females) were screened for CH. SNV profiling (n = 22) spanning three candidate genes, i.e. TSHR, TPO and TG was carried out in confirmed CH cases (n = 45). In screen negative cases (n = 700), ten TSHR variants were explored to establish association with CH. No mutation found in DUOX2. The 2.5th to 97.5th percentiles of TSH in these newborns were 0.5 to 12.2 mU/L. In newborns with optimal birth weight, the cut-off was 10 mU/L. Lower or higher birth weight resulted in slightly higher TSH. Two TSHR variants, i.e. rs7144481 and rs17630128 were associated with agenesis, hypoplasia and goiter. The rs2268477 was associated with agenesis and hypoplasia. The rs1991517, rs2075176 and rs2241119 were associated with agenesis only. The rs7144481, rs17630128, rs1991517 and rs2268477 were associated with 2.17, 4.62, 2.91 and 2.29-fold increased risk for CH, respectively. Among the TPO variants, rs867983 and rs2175977 were associated with agenesis and goiter, respectively. Among the TG variants, rs2076740 showed association with agenesis and goiter. Two rare variants i.e. TPO g.IVS14-19 G>C and TG c.1262 C>T were observed in CH cases. No genetic variant identified in the two exons of DUOX2. To conclude, the current study established Indian population-specific normative values for TSH and demonstrates specific genotype–phenotype correlations among three candidate genes.

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
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Kaur G, Thakur K, Kataria S, Singh TR, Chavan BS, Kaur G, Atwal R (2016) Current and future perspective of newborn screening: an Indian scenario. J Pediatr Endocrinol Metab 29:5–13

    Article  Google Scholar 

  2. Bhatia R, Rajwaniya D (2018) Congenital hypothyroidism screening in term neonates using umbilical cord blood TSH values. Indian J Endocrinol Metab 22:277–279

    Article  Google Scholar 

  3. Christopher R, Radha Rama Devi A, Kabra M, Kapoor S, Mathur R, Muranjan M, Nigam PK, Pandey RM, Singh A, Suresh S (2018) ICMR Task Force on Inherited Metabolic Disorders. Newborn screening for congenital hypothyroidism and congenital adrenal hyperplasia. Indian J Pediatr 85:935–940

    Article  Google Scholar 

  4. Rastogi MV, LaFranchi SH (2010) Congenital hypothyroidism. Orphanet J Rare Dis 5:17

    Article  Google Scholar 

  5. Long W, Zhou L, Wang Y, Liu J, Wang H, Yu B (2020) Complicated relationship between genetic mutations and phenotypic characteristics in transient and permanent congenital hypothyroidism: analysis of pooled literature data. Int J Endocrinol 2020:6808517

    Article  Google Scholar 

  6. Peters C, Nicholas AK, Schoenmakers E, Lyons G, Langham S, Serra EG, Sebire NJ, Muzza M, Fugazzola L, Schoenmakers N (2019) DUOX2/DUOXA2 mutations frequently cause congenital hypothyroidism that evades detection on newborn screening in the United Kingdom. Thyroid 29:790–801

    Article  CAS  Google Scholar 

  7. Kollati Y, Ambati RR, Reddy PN, Kumar NSS, Patel RK, Dirisala VR (2017) Congenital hypothyroidism: facts, facets & therapy. Curr Pharm Des 23:2308–2313

    Article  CAS  Google Scholar 

  8. Agrawal P, Philip R, Saran S, Gutch M, Razi MS, Agroiya P, Gupta K (2015) Congenital hypothyroidism. Indian J Endocrinol Metab 19:221–227

    Article  Google Scholar 

  9. Ramesh BG, Bhargav PR, Rajesh BG, Devi NV, Vijayaraghavan R, Varma BA (2016) Genotype-phenotype correlations of dyshormonogenetic goiter in children and adolescents from South India. Indian J Endocrinol Metab 20:816–824

    Article  CAS  Google Scholar 

  10. Satoh M, Aso K, Ogikubo S, Yoshizawa-Ogasawara A, Saji T (2015) Hypothyroidism caused by the combination of two heterozygous mutations: one in the TSH receptor gene the other in the DUOX2 gene. J Pediatr Endocrinol Metab 28:657–661

    Article  CAS  Google Scholar 

  11. Fang Y, Sun F, Zhang RJ, Zhang CR, Yan CY, Zhou Z, Zhang QY, Li L, Ying YX, Zhao SX, Liang J, Song HD (2019) Mutation screening of the TSHR gene in 220 Chinese patients with congenital hypothyroidism. Clin Chim Acta 497:147–152

    Article  CAS  Google Scholar 

  12. Lee ST, Lee DH, Kim JY, Kwon MJ, Kim JW, Hong YH, Lee YW, Ki CS (2011) Molecular screening of the TSH receptor (TSHR) and thyroid peroxidase (TPO) genes in Korean patients with nonsyndromic congenital hypothyroidism. Clin Endocrinol 75:715–721

    Article  CAS  Google Scholar 

  13. Balmiki N, Bankura B, Guria S, Das TK, Pattanayak AK, Sinha A, Chakrabarti S, Chowdhury S, Das M (2014) Genetic analysis of thyroid peroxidase (TPO) gene in patients whose hypothyroidism was found in adulthood in West Bengal, India. Endocr J 61:289–296

    Article  CAS  Google Scholar 

  14. Rama Devi AR, Naushad SM (2004) Newborn screening in India. Indian J Pediatr 71:157–160

    Article  Google Scholar 

  15. Layon M (2000) GeneTool 1.0: Update 4, Biotech Software & Internet Report. Comput Soft J Scient 1:261–264

    Google Scholar 

  16. Hashemipour M, Soheilipour F, Karimizare S, Khanahmad H, Karimipour M, Aminzadeh S, Kokabee L, Amini M, Hovsepian S, Hadian R (2012) Thyroid peroxidase gene mutation in patients with congenital hypothyroidism in Isfahan, Iran. Int J Endocrinol 2012:717283

    Article  Google Scholar 

  17. Nguyen DT, Choi H, Jo H, Kim J-H, Dirisala VR, Lee K-T, Kim T-H, Park K-K, Seo K, Park C (2011) Molecular characterization of the human ABO blood group orthologus system in pigs. Anim Genet 42(3):325–328

    Article  CAS  Google Scholar 

  18. Kollati Y, Akella RRD, Naushad SM, Thalla M, Reddy GB, Dirisala VR (2020) The rs1991517 polymorphism is a genetic risk factor for congenital hypothyroidism. 3 Biotech 10:285

    Article  Google Scholar 

  19. Grob F, Gutierrez M, Leguizamon L, Fabres J (2020) Hyperthyrotropinemia is common in preterm infants who are born small for gestational age. J Pediatr Endocrinol Metab 33:375–382

    Article  Google Scholar 

  20. Wang H, Kong X, Pei Y, Cui X, Zhu Y, He Z, Wang Y, Zhang L, Zhuo L, Chen C, Yan X (2020) Mutation spectrum analysis of 29 causative genes in 43 Chinese patients with congenital hypothyroidism. Mol Med Rep 22:297–309

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Ahmetov I, Kulemin N, Popov D, Naumov V, Akimov E, Bravy Y, Egorova E, Galeeva A, Generozov E, Kostryukova E, Larin A, Mustafina L, Ospanova E, Pavlenko A, Starnes L, Zmijewski P, Alexeev D, Vinogradova O, Govorun V (2015) Genome-wide association study identifies three novel genetic markers associated with elite endurance performance. Biol Sport 32:3–9

    Article  Google Scholar 

  22. Su X, Lin LW, Weng JL, Chen SW, Yang XH, Zhou DL, Long YK, Shao Q, Ye ZL, Peng JL, Deng L, He CY, Yang AK (2019) TSHR rs2288496 associated with thyroid hormone and predict the occurrence of lymph node metastasis of papillary thyroid cancer. Cancer Biomarkers 26:461–470

    Article  CAS  Google Scholar 

  23. Peeters RP, van Toor H, Klootwijk W, de Rijke YB, Kuiper GG, Uitterlinden AG, Visser TJ (2003) Polymorphisms in thyroid hormone pathway genes are associated with plasma TSH and iodothyronine levels in healthy subjects. J Clin Endocrinol Metab 88:2880–2888

    Article  CAS  Google Scholar 

  24. Al-Deresawi MS (2018) Screening of Mutations in coding region of the Thyroid peroxidase gene in Hypothyroidism patients. J Al-Nisour Univ Collage 5:333–343

    Google Scholar 

  25. Zhang ML, Zhang DM, Wang CE, Chen XL, Liu FZ, Yang JX (2019) Association between thyroglobulin polymorphisms and autoimmune thyroid disease: a systematic review and meta-analysis of case-control studies. Genes Immun 20:484–492

    Article  Google Scholar 

Download references

Acknowledgements

Authors specially thank Dr. Pasumarthi NBS Srinivas, Anusha Puvvada, Uma Maheshwar P for their support during the investigation.

Funding

This work was partly supported by a grant from DST-SERB, Government of India (ECR/2016/00304).

Author information

Author notes

  1. Yedukondalu Kollati and Radha Rama Devi Akella contributed equally to this study.

Authors and Affiliations

  1. Department of Biotechnology, Vignan’s Foundation for Science, Technology & Research (Deemed to be University), Vadlamudi, Guntur, Andhra Pradesh, 522213, India

    Yedukondalu Kollati & Vijaya R. Dirisala

  2. Department of Genetics, Rainbow Children’s Hospital, Banjara Hills, Hyderabad, Telangana, 500009, India

    Radha Rama Devi Akella

  3. Department of Biochemical Genetics and Pharmacogenomics, Sandor Speciality Diagnostics Pvt. Ltd, Banjara Hills, Hyderabad, Telangana, 500034, India

    Radha Rama Devi Akella, Shaik Mohammad Naushad, Divya Borkar & Maunika Thalla

  4. Biochemistry Division, National Institute of Nutrition, Hyderabad, Telangana, 500007, India

    Swapna Nagalingam & G. Bhanuprakash Reddy

  5. Department of Pediatric Neurology, Rainbow Children’s Hospital, Banjara Hills, Hyderabad, Telangana, 500009, India

    Lokesh Lingappa

  6. Department of Genetics, Genetic Group of Gujarat Diagnostic Centre, Mehsana, Gujarat, 384002, India

    Rajesh K. Patel

Authors
  1. Yedukondalu Kollati
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Radha Rama Devi Akella
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shaik Mohammad Naushad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Divya Borkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maunika Thalla
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Swapna Nagalingam
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lokesh Lingappa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rajesh K. Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G. Bhanuprakash Reddy
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Vijaya R. Dirisala
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

VRD, RRDA and SMN designed the work. The work was primarily executed by YK under the supervision of VRD, RRDA and BRG. SMN, DB and MT performed the analysis and interpreted the data. SMN, SN, LL, RKP and BRG gave constructive comments during execution of the work. The manuscript was written by YK and SMN with extensive support of VRD and RRDA. All the authors have given important insights and approved the final version of manuscript.

Corresponding authors

Correspondence to G. Bhanuprakash Reddy or Vijaya R. Dirisala.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study was performed in accordance with the ethical standards of the Institutional Ethics committee of Rainbow Hospital Institutional Ethics Committee (RCHBH/066/02-2018), Hyderabad, India and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed written consents were obtained from parents and participants of all subjects included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOC 153 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kollati, Y., Akella, R.R.D., Naushad, S.M. et al. Newborn screening and single nucleotide variation profiling of TSHR, TPO, TG and DUOX2 candidate genes for congenital hypothyroidism. Mol Biol Rep 47, 7467–7475 (2020). https://doi.org/10.1007/s11033-020-05803-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-020-05803-x

Keywords

Search

Navigation