ESPE Abstracts

The pathogenetic role of genetic factors in congenital hypothyroidism (CH) is now widely known. The constant evolution of diagnostic methods in the field of medical genetics provides the opportunity to obtain an etiological diagnosis in CH patients with genetic defects in candidate genes. We performed genetic analysis by Next Generation Sequencing (NGS) of 18 candidate genes (DUOX2, DUOXA2, FOXE1, GLIS3, IGSF1, IYD, NKX2-1, NKX2-5, PAX8, SLC16A2, SLC26A4, SLC5A5, TG, THRA, THRB, TPO, TSHB, TSHR) involved in both morphogenesis and thyroid function in a selected sample of CH patients. Inclusion criteria were: CH patients with gland-in-situ (GIS), identified by newborn screening from January 2003 to December 2015 in Emilia-Romagna region, with permanent CH emerging from the re-evaluation of the diagnosis. Exclusion criteria were: children with chromosomal abnormalities and the absence of written informed consent. 41 patients (25 males, 16 females) were enrolled. The NGS analysis was carried out using the Ion Torrent S5 Life Technology instrument. Allelic variants (AVs) with MAF <0.05 were included and classified using Varsome. Benign and probably benign AVs were excluded. 36 AVs were detected in 23/41 patients (56%): 13 pts presented with one AV, 7 pts with 2 AVs and 3 pts with 3 AVs. The remaining 18/41 pts were found to be wild-type (WT). 25/36 AVs were found in genes involved in thyroid hormone synthesis: 11 (30.5%) DUOX2; 9 (25%) TG, 3 (8.3%) TPO, 1 SLC26A4, 1 SLC5A5. 10/36 AVs in genes involved in thyroid morphogenesis: 8 (22.2%) TSHR, 1 GLIS3, 1 FOXE1. 1/36 AV in a gene (IGSF1) implicated in the hypothalamic-pituitary function. 50% of the AVs (18/36) were classified as VUS, 28% (10/36) as pathogenic and 22% (8/36) as likely pathogenic, according to the guidelines of the ACMG. In 7 patients (19,4%) we found an oligogenic CH. Among patients who harbored more than one AVs, 3/10 (7%) presented with compound heterozigosity on the same gene and these patients showed a more severe CH (higher TSH and lower fT4 at diagnosis) than those with oligogenic CH (P = 0.017). Despite the preliminary nature of the results, in 56% of patients with CH and GIS we found at least 1 AV of probable pathogenic significance. Further investigations through the search for copy number variations and the analysis of the regulatory regions, currently ongoing, will allow to increase the detection rate and elucidate the mechanisms underlying CH.