ESPE Abstracts (2015) 84 FC13.3

Targeted Next-Generation Sequencing Demonstrates High Frequency of 'Dyshormonogenesis Genes' Mutations in Severe Congenital Hypothyroidism

Nina Makretskayaa, Olga Bezlepkinaa, Anna Kolodkinaa, Alexey Kiyaevb, Evgeny Vasilyeva, Vasily Petrova, Svetlana Kalinenkovac, Olga Duhorevad, Oleg Malievskye, Ivan Dedova & Anatoly Tiulpakova


aEndocrinology Research Centre, Moscow, Russia; bUral State Medical University, Ekaterinburg, Russia; cMoscow Regional Research and Clinical Institute, Moscow, Russia; dMoscow Endocrinology Dispensary, Moscow, Russia; eRepublican Children’s Clinical Hospital, Ufa, Russia


Background: 80–85% of cases of congenital hypothyroidism (CH) are shown to be due to thyroid dysgenesis, while 15–20% are due to dyshormonogenesis. At least 12 candidate genes are associated with congenital hypothyroidism (CH), however its molecular basis is defined in fewer than 10% of the patients (ESPE consensus, 2014). Recent studies suggest that using a next generation sequencing (NGS) approach may increase the mutation yield in CH.

Objective and hypotheses: To define molecular basis of severe CH using a targeted NGS.

Methods: 198 CH patients (males, n=70; females, n=128; TSH level on neonatal screening more than 90 mU/l) and 35 control subjects were studied. ‘Thyroid panel’ genes were sequenced using a custom Ion Ampliseq gene panel and PGM semiconductor sequencer (Ion Torrent). Non-synonymous sequence variants were rated as ‘probably pathogenic’ if they had allele frequency <1% and pathogenic ljb database scores (ANNOVAR).

Results: 129 pathogenic or probably pathogenic mutations were found in 51% of the patients (n=100) and in 11% of controls. 18 mutations (14%) were detected in genes associated with thyroid gland dysgenesis: TSHR, n=6; PAX8, n=5; NKX2-1, n=4; NKX2-5, n=3; FOXE1, n=0. 111 mutations (86%) were found in genes associated with dyshormonogenesis: TG, n=39; DUOX2, n=29; TPO, n=27; SLC26A4, n=7; IYD, n=5; SLC5A5, n=3; DOUXA2; n=1. 19 patients showed mutations in two or three genes. The majority of mutations in ‘dyshormonogenesis genes’ were monoallelic.

Conclusion: The results demonstrate high frequency of mutations in genes associated with dyshormonogenesis. The molecular findings were consistent with the phenotype only in one third of the cases, which implies that other mutations/factors may play a role in development of CH.

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