AUTHOR=Yang Rulai , Lu Yijun , Yang Chenxi , Wu Xiaoyu , Feng Junqi , Zhu Ling , Shu Qiang , Jiang Pingping 

TITLE=Case Report: Expanding the Digenic Variants Involved in Thyroid Hormone Synthesis−10 New Cases of Congenital Hypothyroidism and a Literature Review

JOURNAL=Frontiers in Genetics

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.694683

DOI=10.3389/fgene.2021.694683

ISSN=1664-8021

ABSTRACT=<p>Congenital hypothyroidism (CH) is the most common neonatal metabolic disorder. Although it has been understood to be a monogenic disease, some CH patients are reported to carry two or more variants at different genes. Here, ten permanent congenital hypothyroidism (PCH) patients were retrospectively reviewed, with elevated levels of serum thyroid-stimulating hormone and levothyroxine dependence during follow-up between 2015 and 2019. Each affected individual carried digenic variants, which were heterozygous at two of pathogenic genes. In total, five pathogenic genes, <italic>TSHR, TG, TPO, DUOX2</italic> and <italic>DUOXA2</italic>, were simultaneously identified in subjects that were involved in the same metabolic pathway: thyroid hormone biosynthesis. There were digenic variants at TSHR and DUOX2 combined in three patients, <italic>DUOX2</italic> and <italic>TG</italic> combined in two patients, <italic>DUOX2</italic> and <italic>DUOXA2</italic> combined in two patients, <italic>TG</italic> and <italic>DUOXA2</italic> combined in two patients, and <italic>TG</italic> and <italic>TPO</italic> combined in one patient. Additionally, seven novel variants, <italic>TSHR</italic> c.679G&gt;A, <italic>DUOX2</italic> c.127A&gt;T, c.608-619del, c.959T&gt;C, <italic>TG</italic> c.2307G&gt;A, and c.6759_6765del, and <italic>DUOXA2</italic> c.93T&gt;G, were identified in these PCH patients. Along with a literature review on digenic variants in patients with CH, our findings illustrated the complexity of genetic etiology in CH.</p>