ESPE Abstracts

Background and Objective: Congenital hypothyroidism (CH) is mostly detected with neonatal newborn screening (NBS). CH is the most common neonatal endocrine disorder with an incidence of 1:2,000-1:4,000. However the molecular etiology is sill poorly understood, considering pathogenic variations in candidate genes have been found only in 10-20 % of CH. We performed mutations screening of causative genes through a systematic Next Generation Sequencing (NGS) analysis in CH cases with positive NBS results.

Methods: We performed the genetic analysis of causative 59 genes using NGS in 168 CH cases (53 dyshormonogenesis, 32 dysgenesis, 83 not evaluated). Pathogenicity of novel mutations was assessed in silico.

Results: We identified 12.5 % (21/168) and 5.4 % (9/168) with seemingly monogenic defects and oligogenic defects, respectively. Monogenic defects (21 cases) involved DUOX2 (12), TSHR (5), TG (2), and PAX8 (2). Oligogenic defects (9 cases) had two mutations in two different genes among DUOX2, TG, TSHR, SLC16A2, GLIS3, TPO, SECISBP2, DUOXA1, and SLC26A4.

Discussion: This study identified 12.5 % of monogenic defects in NBS-positive CH, which is similar result as previously reported. In addition, we found 5.4 % in CH patients having oligogenic defects. The role of oligogenicity in etiology of CH remains unclear, however frequent occurrence of several mutations in two or more candidate genes suggest the contribution of oligogenic variants. The systematic NGS analysis is useful in determining an underlying moleculer etiology of CH.