APPLICATION OF TARGETED NEXT-GENERATION SEQUENCING AND SINGLE-GENE ANALYSIS TO THE MOLECULAR DIAGNOSTICS OF CONGENITAL HYPOTHYROIDISM

ANA CHIESA; PAULA SCAGLIA; VIRGINIE JACQUES; ROMINA CELESTE GEYSELS; PATRICIA PAPENDIECK; FRÉDÉRIQUE SAVAGNER; VICTORIA PEYRET; JUAN PABLO NICOLA ; HORACIO DOMENE; MANON CASSOU; MARIANO MARTIN

Buenos Aires

Congreso; LXII Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica; 2017

Sociedad Argentina de Investigación Clínica

Congenital hypothyroidism (CH) is the most frequent endocrinedisorder in pediatric patients with an incidence of 1:2,000-4,000newborns. Thirty monogenic forms of CH have been reported, highlightingthe genetic heterogeneity of the disease. A meta-analysisdemonstrated that only 5-10% of patients with thyroid dysgenesis(TDG) and 45-88% of patients with thyroid dyshormonogenesis(TDH) are diagnosed using single-gene analysis (SGA). Here, weused targeted next-generation sequencing (TNGS) and SGA to investigatethe etiology of CH.TNGS was used to analyze the coding sequence of 17 candidategenes involved in the pathogenesis of CH in patients with TDG(n=2) or TDH (n=10). Additionally, we evaluated slc5a5 (NIS) codingsequence using Sanger sequencing in patients (n=3) with a clinicalphenotype of iodide transport defect (ITD), a cause of TDH.Among patients studied by TNGS, 7 (58%) presented simple orcompound heterozygous variants in genes involved in TDG or TDH.No homozygous variants or small gene deletion/insertions wereevidenced. One patient with thyroid dysgenesis showed a heterozygousFOXE1 variant (p.P203R). In addition, one patient withthyroid dyshormonogenesis showed compound heterozygous TGvariants (p.D29X/c.177-2A>C). The remaining patients with thyroiddyshormonogenesis showed simple heterozygous TG (p.F1542Vfs*20; p.T2563C; p.S523P) or DUOX2 (p.E1496Dfs*51; p.W178L)variants. None of the patients under analysis presented variations inmore than one gene involved in TDH. Of note, all 3 patients with ITDshowed compound heterozygous NIS variants (p.Q136L/ p.D369;p.L562M/p.G543K; p.D331N/p.S547R). All identified variants werepredicted pathogenic or reported as pathogenic in the literature.TGNS constitutes an attractive alternative to systematically exploreand diagnose CH, particularly when the clinical and biochemicalphenotype is unclear for SGA. However, we evidenced that a considerableproportion of patients (42%) remain genetically undiagnosed.