High frequency of mutations in 'dyshormonogenesis genes' in severe congenital hypothyroidism

PLoS One. 2018 Sep 21;13(9):e0204323. doi: 10.1371/journal.pone.0204323. eCollection 2018.


Objective: Results of the screening of disease causative mutations in congenital hypothyroidism (CH) vary significantly, depending on the sequence strategy, patients' inclusion criteria and bioinformatics. The objective was to study the molecular basis of severe congenital hypothyroidism, using the next generation sequencing (NGS) and the recent guidelines for assessment of sequence variants.

Design: 243 patients with CH (TSH levels at neonatal screening or retesting greater than 90 mU/l) and 56 control subjects were included in the study.

Methods: A custom NGS panel targeting 12 CH causative genes was used for sequencing. The sequence variants were rated according to American College of Medical Genetics and Genomics (ACMG) guidelines.

Results: In total, 48 pathogenic, 7 likely pathogenic and 57 variants of uncertain significance were identified in 92/243 patients (37.9%), while 4 variants of uncertain significance were found in 4/56 control subjects (7.1%). 13.1% (12/92) of the cases showed variants in 'thyroid dysgenesis' (TD) genes: TSHR, n = 6; NKX2-1, n = 2; NKX2-5, n = 1; PAX8, n = 3. The variants in 'dyshormonogenesis' (DH) genes were found in 84.8% (78/92) of cases: TPO, n = 30; DUOX2, n = 24; TG, n = 8; SLC5A5, n = 3; SLC26A4, n = 6; IYD, n = 1. 8 patients showed oligonenic variants. The majority of variants identified in DH genes were monoallelic.

Conclusions: In contrast to earlier studies demonstrating the predominance of TD in severe CH, the majority of variants identified in our study were in DH genes. A large proportion of monoallelic variants detected among DH genes suggests that non-mendelian mechanisms may play a role in the development of CH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Autoantigens / genetics
  • Child
  • Child, Preschool
  • Congenital Hypothyroidism / genetics*
  • Congenital Hypothyroidism / pathology*
  • Dual Oxidases / genetics
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Infant
  • Iodide Peroxidase / genetics
  • Iron-Binding Proteins / genetics
  • Male
  • Multiplex Polymerase Chain Reaction
  • Polymorphism, Genetic
  • Receptors, Thyrotropin / genetics
  • Sequence Analysis, DNA
  • Severity of Illness Index
  • Sulfate Transporters / genetics
  • Thyroid Nuclear Factor 1 / genetics


  • Autoantigens
  • Iron-Binding Proteins
  • NKX2-1 protein, human
  • Receptors, Thyrotropin
  • SLC26A4 protein, human
  • Sulfate Transporters
  • Thyroid Nuclear Factor 1
  • Dual Oxidases
  • TPO protein, human
  • Iodide Peroxidase
  • DUOX2 protein, human

Grants and funding

This work was supported by Alfa-Endo Program of Charities Aid Foundation (CAF) Russia.