Background: Dyshormonogenic hypothyroidism is classically a monogenic disease with recessive inheritance. Thyroid dysgenesis showed a multigenic origin in a mouse model of double-heterozygous deletions of Nkx2.1/Pax8 transcription factor genes, suggesting a possible polygenic nature of certain cases of human hypothyroidism.
Objective and Hypotheses: To investigate genetic traits of polygenic involvement in dyshormonogenic hypothyroidism, using next generation sequencing (NGS).
Methods: Endocrine and genetic characterization of four pedigrees with thyroid dyshormonogenesis. NGS of 18 thyroidal genes including TG, TPO, DUOX2/DUOXA2 and DEHAL1. Pathogenicity prediction and H2O2-generation testing of mutants.
Results: Three families (F1F3) were consanguineous. All patients showed positive perchlorate discharge (PD). In F1, two siblings with congenital hypothyroidism (TSH>200 mu/l) had elevated thyroglobulin (>1600 ng/ml) and 100% PD. NGS revealed a homozygous frameshift mutation in TPO (p.S756fsX75) in both brothers. Additionally, one presented a heterozygous nonsense mutation in DUOX2 (p.K530X). In F2, two sisters were born with increased neonatal TSH (200 and 800 mu/l). Both were homozygotes for a nonsense TG mutation (p.R296X) but also were respectively heterozygote and homozygote for a pathogenic TPO mutation (p.G667S). In F3, index patient presented neonatal TSH>800 mu/l, thyroglobulin >300 ng/ml and 30% PD. NGS revealed a yet described pathogenic homozygous TPO mutation (p.G493S) and a rare heterozygous TG change (p.G653D) predicted as highly pathogenic. In non-consanguineous F4, two sisters had pubertal euthyroid/hyperthyrotropinemic goiters and 25% PD. Both were heterozygotes for a known pathogenic TPO mutation (p.N425S), but one also presented a heterozygous DUOXA2 mutation (p.G294E) which reduced 50% the in vitro capacity of H2O2 generation by DUOX2-DUOXA2 pair.
Conclusion: Targeted NGS reveals unexpected mutations additional to typical homozygous defects in consanguineous children with thyroid dyshormonogenesis. These additional mutations occur in genes also involved in iodide organification (DUOX2, TPO, TG, DUOXA2), had not been identified by standard one-gene-approach sequencing and may account for the intra-familial phenotypic variability of dyshormonogenic hypothyroidism.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology