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. 2022 Apr;45(4):773-786. doi: 10.1007/s40618-021-01706-1. Epub 2021 Nov 15.


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.

Keywords: Congenital hypothyroidism; Goiter; Next-generation sequencing; TPO; Thyroid dyshormonogenesis.

MeSH terms

  • Antiporters / analysis
  • Antiporters / blood
  • Antiporters / genetics
  • Child
  • Child, Preschool
  • Congenital Hypothyroidism / genetics*
  • Dual Oxidases / analysis
  • Dual Oxidases / blood
  • Dual Oxidases / genetics
  • Female
  • Forkhead Transcription Factors / analysis
  • Forkhead Transcription Factors / blood
  • Forkhead Transcription Factors / genetics
  • Genetic Variation / genetics*
  • High-Throughput Nucleotide Sequencing / methods
  • High-Throughput Nucleotide Sequencing / statistics & numerical data
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Receptors, Thyrotropin / analysis
  • Receptors, Thyrotropin / blood
  • Receptors, Thyrotropin / genetics
  • Sulfate Transporters / analysis
  • Sulfate Transporters / blood
  • Sulfate Transporters / genetics
  • Thyroglobulin / analysis
  • Thyroglobulin / blood
  • Thyroglobulin / genetics


  • Antiporters
  • FOXE1 protein, human
  • Forkhead Transcription Factors
  • Receptors, Thyrotropin
  • SLC26A7 protein, human
  • Sulfate Transporters
  • TG protein, human
  • TSHR protein, human
  • Thyroglobulin
  • Dual Oxidases
  • DUOX2 protein, human