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Screening of 23 candidate genes by next-generation sequencing of patients with permanent congenital hypothyroidism: novel variants in TG, TSHR, DUOX2, FOXE1, and SLC26A7

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Abstract

Purpose

To date, many genes have been associated with congenital hypothyroidism (CH). Our aim was to identify the mutational spectrum of 23 causative genes in Turkish patients with permanent CH, including thyroid dysgenesis (TD) and dyshormonogenesis (TDH) cases.

Methods

A total of 134 patients with permanent CH (130 primary, 4 central) were included. To identify the genetic etiology, we screened 23 candidate genes associated with CH by next-generation sequencing. For confirmation and to detect the status of the specific familial variant in relatives, Sanger sequencing was also performed.

Results

Possible pathogenic variants were found in 5.2% of patients with TD and in 64.0% of the patients with normal-sized thyroid or goiter. In all patients, variants were most frequently found in TSHR, followed by TPO and TG. The same homozygous TSHB variant (c.162 + 5G > A) was identified in four patients with central CH. In addition, we detected novel variants in the TSHR, TG, SLC26A7, FOXE1, and DUOX2.

Conclusion

Genetic causes were determined in the majority of CH patients with TDH, however, despite advances in genetics, we were unable to identify the genetic etiology of most CH patients with TD, suggesting the effect of unknown genes or environmental factors. The previous studies and our findings suggest that TSHR and TPO mutations is the main genetic defect of CH in the Turkish population.

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Acknowledgements

We would like to thank the children and their parents who participated in this study. We also would like to thank Enago (www.enago.com) for the English language review.

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This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

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Authors and Affiliations

  1. Division of Pediatric Endocrinology, Dr. Behçet Uz Children’s Education and Research Hospital, İsmet Kaptan Mh, Sezer Doğan Sokağı No:11, 35210, Konak/Izmir, Turkey

    S. Acar, G. Arslan, Ö. Nalbantoğlu, Ö. Köprülü, B. Özkaya & B. Özkan

  2. Division of Pediatric Genetics, Dr. Behçet Uz Children’s Education and Research Hospital, Izmir, Turkey

    S. Gürsoy

  3. Department of Medical Genetics, Dr. Behçet Uz Children’s Education and Research Hospital, Izmir, Turkey

    F. Hazan

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Contributions

SA, BÖ, SA, and GA conducted the study. SA and SG coordinated all steps of this study. SA, SG, GA, ÖN, FH, ÖK, BÖ, and BÖ contributed to the study conception and design and analysis and interpretation of and reviewed this paper. All of the authors approved the final version of this work.

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Correspondence to S. Acar.

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This study was approved by the local ethics committee in light of the Helsinki Declaration (2020/12-03).

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Acar, S., Gürsoy, S., Arslan, G. et al. Screening of 23 candidate genes by next-generation sequencing of patients with permanent congenital hypothyroidism: novel variants in TG, TSHR, DUOX2, FOXE1, and SLC26A7. J Endocrinol Invest 45, 773–786 (2022). https://doi.org/10.1007/s40618-021-01706-1

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