APPLICATION OF TARGETED NEXT GENERATION SEQUENCING TO THE MOLECULAR DIAGNOSTICS OF CONGENITAL HYPOTHYROIDISM

JACQUES, V; TESTA, G; DOMENE, H; NICOLA, JP; SAVAGNER, F; SIGNORINO, M; SCAGLIA, P; CHIESA, A; CASSOU, M; MIRAS, M; PAPENDIECK, P

Rio de Janeiro

Congreso; XVI Congreso de la Sociedad Latinoamericana de Tiroides; 2017

Sociedad Latinoamericana de Tiroides

Introduction: Congenital hypothyroidism is the most frequent endocrine disorder in pediatric patients with an incidence of 1:2,000-4,000 newborns. Thirty monogenic forms of congenital hypothyroidism have been reported in individuals with congenitalhypothyroidism, highlighting the genetic heterogeneity of the disease. Objective: A meta-analysis demonstrated that only 5%-10% of patients with thyroid dysgenesis and 45%-88% of patients with thyroid dyshormonogenesis are diagnosed usingsingle-gene sequencing. Here, we used targeted next generation sequencing approach to investigate the etiology of congenital hypothyroidism. Material and methods: Genomic DNA from 13 pediatric patients with permanent congenital hypothyroidismdue to thyroid dysgenesis (n = 2) or dyshormonogenesis (n = 11) was explored by targeted next generation sequencing to analyze the coding sequence of 17 candidate genes (TG, TPO, DUOXA2, DUOX2, SLC5A5, SLC16A2, SLC26A4, TSHR, GNAS1, THRB, THRA, PAX8, NKX2.1, NKX2.5, FOXE1, IYD, SECISBP2) involved in the pathogenesis of congenital hypothyroidism. Results and conclusions: Among all 13 patients studied, 7 (54%) presented simple or compound heterozygous variants in genes involved in thyroid organogenesis or hormonogenesis. No homozygous variants or small gene deletion/insertions were evidenced. One patient with thyroid dysgenesis showed a heterozygous FOXE1 variant (p.P203R). In addition, one patient with thyroid dyshormonogenesis showed compound heterozygous TG variants (p.D29X; c.177-2A>C). The remaining patients with thyroid dyshormonogenesis showed simple heterozygous TG (p.F1542Vfs*20; p.T2563C; p.S523P) or DUOX2 (p.E1496Dfs*51; p.W178L) variants. All identified variants were predicted pathogenic or reported as pathogenic in the literature. Of note, none of the 13 patients under study presented variations in more than one gene involved in thyroidhormonogenesis. Surprisingly, most of the patients evidenced a significantly loose correlation between clinical phenotype and genotype. Targeted next-generation sequencing constitutes an attractive alternative to systematically explore and diagnosecongenital hypothyroidism. However, we evidenced that a considerable proportion of patients (46%) remain undiagnosed. Further molecular analysis, such as whole-exome sequencing, may provide novel insights into the pathogenesis of congenitalhypothyroidism.