Abstract
Background: Thyroid dysgenesis (TD), which is caused by gland developmental abnormalities, is the most common cause of congenital hypothyroidism (CH). In addition, advances in diagnostic techniques have facilitated the identification of mild CH patients with a gland-in-situ (GIS) with normal thyroid morphology. Therefore, TD and GIS account for the vast majority of CH cases.Methods: Sixteen known genes to be related to CH were sequenced and screened for variations by next-generation sequencing (NGS) in a cohort of 377 CH cases, including 288 TD cases and 89 GIS cases.Results: In our CH cohort, we found that DUOX2 (21.22%) was the most commonly variant pathogenic gene, while DUOXA2 was prominent in TD (18.75%) and DUOX2 was prominent in GIS (34.83%). Both biallelic and triple variants of DUOX2 were found to be most common in children with TD and children with GIS. The most frequent combination was DUOX2 with DUOXA1 among the 61 patients who carried digenic variants. We also found for the first time that biallelic TG, DUOXA2, and DUOXA1 variants participate in the pathogenesis of TD. In addition, the variant p.Y246X in DUOXA2 was the most common variant hotspot, with 58 novel variants identified in our study.Conclusion: We meticulously described the types and characteristics of variants from sixteen known gene in children with TD and GIS in the Chinese population, suggesting that DUOXA2 and DUOX2 variants may confer susceptibility to TD and GIS via polygenic inheritance and multiple factors, which further expands the genotype-phenotype spectrum of CH in China.
Highlights
Congenital hypothyroidism (CH), a common childhood disease associated with mental disabilities, manifests as high thyroid-stimulating hormone (TSH) levels and low T4 levels in the serum during neonatal screening due to insufficient production of thyroid hormone
Genetic Screening of Congenital Hypothyroidism neonatal screening program that started in 1984, CH affected up to 1/2421 neborns (4.13 per 10,000 live births) between 2013 and 2015, compared to 1/3000–1/4000 newborns worldwide; these figures suggest a high incidence in China and prompted us to investigate the pathogenesis of this disease [5,6,7]
CH was diagnosed according to high TSH (> 4.2 μIU/ml) and low FT4 (< 12 μpmol/L). [3] The morphological classification of thyroid is as follows: (a) GIS means a child diagnosed with CH, accompanied by normal thyroid anatomy and imaging findings; (b) athyreosis is defined as failure to show any thyroid tissue on ultrasonography and technetium thyroid scans; (c) ectopia refers to the absence of thyroid tissue in normal thyroid anatomical structure, but appeared in other areas; (d) hypoplasia refers to unilateral and/or bilateral thyroid gland not reaching normal size and lacking normal shape [27]
Summary
Congenital hypothyroidism (CH), a common childhood disease associated with mental disabilities, manifests as high thyroid-stimulating hormone (TSH) levels and low T4 levels in the serum during neonatal screening due to insufficient production of thyroid hormone. Genetic Screening of Congenital Hypothyroidism neonatal screening program that started in 1984, CH affected up to 1/2421 neborns (4.13 per 10,000 live births) between 2013 and 2015, compared to 1/3000–1/4000 newborns worldwide; these figures suggest a high incidence in China and prompted us to investigate the pathogenesis of this disease [5,6,7]. Gland-in-situ (GIS) with normal thyroid morphology and goiter were once thought to be present in only 20–30% of CH patients, an increase in the frequency of CH with GIS has been reported, with the incidence more than doubled to ∼1 in 1,500 live newborns, which accounted for almost two-thirds of diagnosed cases in Italy at the time [11, 12]. TD and GIS account for the vast majority of CH cases
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