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Mutation screening of eight genes and comparison of the clinical data in a Chinese cohort with congenital hypothyroidism

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Abstract

Background

Congenital hypothyroidism (CH) is a common neonatal endocrine disorder, characterized by irreversible intellectual disability and short stature if left untreated. It can be divided into thyroid dysgenesis (TD), including athyreosis, ectopy and hypoplasia, and dyshormonogenesis (DH), also referring to gland in situ (GIS), in which patients have eutopic thyroids with normal size or goiter. This study aims to analyze the clinical and genetic data of 375 Chinese CH patients without DUOX2 and thyroid transcription factor (TTF) variants, and to explore the mutation frequencies of the eight genes and the inheritance pattern of CH.

Methods

Targeted next generation sequencing (NGS) and statistical analysis were performed for mutation screening on eight CH-related genes and the comparison of clinical data in a cohort of 606 Chinese CH patients from Henan Province.

Results

A total of 104 variants were detected in genes required for thyroid formation (TSHR, GLIS3, BOREALIN, NTN1, JAG1 and TUBB1) and thyroid hormone synthesis (TG and TPO) in 83 subjects. Monogenic variants were the most prevalent with a percentage of 75.00% (78/104) followed by oligogenic variants (25.00%, 26/104). No differences were found in various clinical data between patients with and without variants. However, it should be noted that only initial L-T4 dose was statistically different between patients with monogenic variants and oligogenic variants.

Conclusions

Our results suggested that apart from Mendelian monogenic inheritance, oligogenic inheritance of CH could not be excluded and also involves other factors, such as penetrance, epigenetic mechanisms and environmental factors.

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Data availability

The data analyzed during this study are available from the corresponding authors upon reasonable request.

References

  1. A. Stoupa et al. New genetics in congenital hypothyroidism. Endocrine 71, 696–705 (2021). https://doi.org/10.1007/s12020-021-02646-9

    Article  CAS  Google Scholar 

  2. F. Sun et al. The genetic characteristics of congenital hypothyroidism in China by comprehensive screening of 21 candidate genes. Eur. J. Endocrinol. 178, 623–633 (2018). https://doi.org/10.1530/eje-17-1017

    Article  CAS  Google Scholar 

  3. G. Tuli et al. Incidence of primary congenital hypothyroidism and relationship between diagnostic categories and associated malformations. Endocrine 71, 122–129 (2021). https://doi.org/10.1007/s12020-020-02370-w

    Article  CAS  Google Scholar 

  4. A. Weiner, S. Oberfield, P. Vuguin, The laboratory features of congenital hypothyroidism and approach to therapy. Neoreviews 21, e37–e44 (2020). https://doi.org/10.1542/neo.21-1-e37

    Article  Google Scholar 

  5. L. Li et al. Identification and analyzes of DUOX2 mutations in two familial congenital hypothyroidism cases. Endocrine 72, 147–156 (2021). https://doi.org/10.1007/s12020-020-02437-8

    Article  CAS  Google Scholar 

  6. M. Castanet et al. Familial forms of thyroid dysgenesis among infants with congenital hypothyroidism. N. Engl. J. Med. 343, 441–442 (2000). https://doi.org/10.1056/nejm200008103430614

    Article  CAS  Google Scholar 

  7. L. Sindhuja, D. Dayal, K. Sodhi, N. Sachdeva, A. Bhattacharya, Thyroid dysfunction and developmental anomalies in first degree relatives of children with thyroid dysgenesis. World J. pediatrics: WJP 12, 215–218 (2016). https://doi.org/10.1007/s12519-015-0061-z

    Article  CAS  Google Scholar 

  8. H. Grasberger, S. Refetoff, Genetic causes of congenital hypothyroidism due to dyshormonogenesis. Curr. Opin. pediatrics 23, 421–428 (2011). https://doi.org/10.1097/MOP.0b013e32834726a4

    Article  CAS  Google Scholar 

  9. H. Cangul et al. Homozygous loss-of-function mutations in SLC26A7 cause goitrous congenital hypothyroidism. JCI Insight 3, (2018). https://doi.org/10.1172/jci.insight.99631

  10. A. Stoupa et al. Thyroid Hypoplasia in Congenital Hypothyroidism Associated with Thyroid Peroxidase Mutations. Thyroid 28, 941–944 (2018). https://doi.org/10.1089/thy.2017.0502

    Article  CAS  Google Scholar 

  11. A. Bauer, A. Wassner, Thyroid hormone therapy in congenital hypothyroidism and pediatric hypothyroidism. Endocrine 66, 51–62 (2019). https://doi.org/10.1007/s12020-019-02024-6

    Article  CAS  Google Scholar 

  12. P. van Trotsenburg et al. Congenital Hypothyroidism: A 2020–2021 Consensus Guidelines Update—An ENDO-European Reference Network Initiative Endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology. Thyroid 31, 387–419 (2021). https://doi.org/10.1089/thy.2020.0333

    Article  Google Scholar 

  13. J.J. Bongers-Schokking, W.C. Resing, Y.B. de Rijke, M.A. de Ridder, S.M. de Muinck Keizer-Schrama, Cognitive development in congenital hypothyroidism: is overtreatment a greater threat than undertreatment. J. Clin. Endocrinol. Metab. 98, 4499–4506 (2013). https://doi.org/10.1210/jc.2013-2175

    Article  CAS  Google Scholar 

  14. F. Wang, L. **aole, R. Ma, D. Zhao, & S. Liu, Dual Oxidase System Genes Defects in Children With Congenital Hypothyroidism. Endocrinology 162, (2021). https://doi.org/10.1210/endocr/bqab043

  15. L. Li et al. Molecular and clinical characteristics of congenital hypothyroidism in a large cohort study based on comprehensive thyroid transcription factor mutation screening in Henan. Clin. Chim. Acta 518, 162–169 (2021). https://doi.org/10.1016/j.cca.2021.03.015

    Article  CAS  Google Scholar 

  16. X. Fan et al. Next-generation sequencing analysis of twelve known causative genes in congenital hypothyroidism. Clin. Chim. acta; Int. J. Clin. Chem. 468, 76–80 (2017). https://doi.org/10.1016/j.cca.2017.02.009

    Article  CAS  Google Scholar 

  17. S. Richards 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. Genet Med 17, 405–424 (2015). https://doi.org/10.1038/gim.2015.30

    Article  Google Scholar 

  18. Y. Watanabe et al. Congenital Hypothyroidism due to Oligogenic Mutations in Two Sudanese Families. Thyroid 29, 302–304 (2019). https://doi.org/10.1089/thy.2018.0295

    Article  CAS  Google Scholar 

  19. M. Satoh, K. Aso, S. Ogikubo, A. Yoshizawa-Ogasawara, T. Saji, 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 (2015). https://doi.org/10.1515/jpem-2014-0078

    Article  CAS  Google Scholar 

  20. Z. Aycan et al. Digenic DUOX1 and DUOX2 Mutations in Cases With Congenital Hypothyroidism. J. Clin. Endocrinol. Metab. 102, 3085–3090 (2017). https://doi.org/10.1210/jc.2017-00529

    Article  Google Scholar 

  21. T. de Filippis et al. A frequent oligogenic involvement in congenital hypothyroidism. Hum. Mol. Genet. 26, 2507–2514 (2017). https://doi.org/10.1093/hmg/ddx145

    Article  CAS  Google Scholar 

  22. N. Makretskaya et al. High frequency of mutations in ‘dyshormonogenesis genes’ in severe congenital hypothyroidism. PloS one 13, e0204323 (2018). https://doi.org/10.1371/journal.pone.0204323

    Article  CAS  Google Scholar 

  23. K. Abe et al. Association between monoallelic TSHR mutations and congenital hypothyroidism: a statistical approach. Eur. J. Endocrinol. 178, 137–144 (2018). https://doi.org/10.1530/EJE-16-1049

    Article  CAS  Google Scholar 

  24. Z. Sasivari, G. Szinnai, B. Seebauer, D. Konrad, M. Lang-Muritano, Double variants in TSHR and DUOX2 in a patient with hypothyroidism: case report. J. Pediatr. Endocrinol. Metab. 32, 1299–1303 (2019). https://doi.org/10.1515/jpem-2019-0051

    Article  CAS  Google Scholar 

  25. T. Yamaguchi et al. Targeted next-generation sequencing for congenital hypothyroidism with positive neonatal TSH screening. J. Clin. Endocrinol. Metab. 105, e2825–e2833 (2020). https://doi.org/10.1210/clinem/dgaa308

    Article  Google Scholar 

  26. I. Oliver-Petit et al. Next-generation sequencing analysis reveals frequent familial origin and oligogenism in congenital hypothyroidism with dyshormonogenesis. Fronti. Endocrinol. 12, (2021). https://doi.org/10.3389/fendo.2021.657913

  27. A. Nicholas et al. Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ. J. Clin. Endocrinol. Metab. 101, 4521–4531 (2016). https://doi.org/10.1210/jc.2016-1879

    Article  CAS  Google Scholar 

  28. Y. Fang et al. Mutation screening of the TSHR gene in 220 Chinese patients with congenital hypothyroidism. Clin. Chim. acta; Int. J. Clin. Chem. 497, 147–152 (2019). https://doi.org/10.1016/j.cca.2019.07.031

    Article  CAS  Google Scholar 

  29. R.J. Zhang et al. Molecular and clinical genetics of the transcription factor GLIS3 in Chinese congenital hypothyroidism. Mol. Cell Endocrinol. 528, 111223 (2021). https://doi.org/10.1016/j.mce.2021.111223

    Article  CAS  Google Scholar 

  30. T. de Filippis et al. JAG1 Loss-Of-Function Variations as a Novel Predisposing Event in the Pathogenesis of Congenital Thyroid Defects. J. Clin. Endocrinol. Metab. 101, 861–870 (2016). https://doi.org/10.1210/jc.2015-3403

    Article  CAS  Google Scholar 

  31. A. Carre et al. Mutations in BOREALIN cause thyroid dysgenesis. Hum. Mol. Genet 26, 599–610 (2017). https://doi.org/10.1093/hmg/ddw419

    Article  CAS  Google Scholar 

  32. A. Stoupa et al. TUBB1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology. EMBO Mol Med 10, (2018). https://doi.org/10.15252/emmm.201809569

  33. A. Carré et al. Mutations in BOREALIN cause thyroid dysgenesis. Hum. Mol. Genet. ddw419, 599–610 (2016). https://doi.org/10.1093/hmg/ddw419

  34. N. Zdraveska, M. Kocova, A.K. Nicholas, V. Anastasovska, N. Schoenmakers, Genetics of gland-in-situ or hypoplastic congenital hypothyroidism in Macedonia. Front Endocrinol. (Lausanne) 11, 413 (2020). https://doi.org/10.3389/fendo.2020.00413

    Article  Google Scholar 

  35. H. Cangul et al. Novel truncating thyroglobulin gene mutations associated with congenital hypothyroidism. Endocrine 45, 206–212 (2014). https://doi.org/10.1007/s12020-013-0027-7

    Article  CAS  Google Scholar 

  36. C. Fu et al. Next-generation sequencing analysis of TSHR in 384 Chinese subclinical congenital hypothyroidism (CH) and CH patients. Clin. Chim. Acta 462, 127–132 (2016). https://doi.org/10.1016/j.cca.2016.09.007

    Article  CAS  Google Scholar 

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Acknowledgements

We thank all contributors for their participation.

Author contributions

L.L. wrote the manuscript, X.L. and D.Z. provided clinical samples and data, X.W. and M.H. analyzed the data, S.L. and F.W. constructed the study design. All authors approved the final version of the manuscript.

Funding

This work was supported by the National Key Research and Development Program of China under Grant no. 2016YFC1000306 and Joint Construction Project of Medical Science and Technology Research Plan of Henan Province in 2019 under Grant no. LHGJ20190357.

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Author notes

  1. These authors contributed equally: Liangshan Li, **aole Li

Authors and Affiliations

  1. Medical Genetic Department, the Affiliated Hospital of Qingdao University, Qingdao, China

    Liangshan Li, **aoyu Wang, Mengmeng Han & Shiguo Liu

  2. Department of Clinical Laboratory, Huadong Hospital affiliated to Fudan University, Shanghai, China

    Liangshan Li

  3. Department of Henan Newborn Screening Center, the Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    **aole Li & Dehua Zhao

  4. Endocrinology Department, the Affiliated Hospital of Qingdao University, Qingdao, China

    Fang Wang

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  1. Liangshan Li
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Correspondence to Fang Wang or Shiguo Liu.

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Li, L., Li, X., Wang, X. et al. Mutation screening of eight genes and comparison of the clinical data in a Chinese cohort with congenital hypothyroidism. Endocrine 79, 125–134 (2023). https://doi.org/10.1007/s12020-022-03188-4

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