Zhang Cheng-Cheng, Zhang Wen-Ting, Chen Li-Hua, Deng Mei, Tian Jing-Li, Liu Rui, Ma Jing-Jing, Huang Xiao-Ling, Song Yuan-Zong
Department of Pediatrics, The First Affiliated Hospital, Jinan University, No.613, Huangpu Avenue West, Tianhe District, Guangzhou, Guangdong 510630, China.
Neonatal Screening Center, Dongguan Maternal and Child Healthcare Hospital, No.99, Zhenxing Road, Dongcheng Street, Dongguan, Guangdong 523000, China; Dongguan Key Laboratory of Screening, Diagnosis and Treatment of Neonatal Genetic and Metabolic Diseases, No.99, Zhenxing Road, Dongcheng Street, Dongguan, Guangdong 523000, China.
Clin Chim Acta. 2025 Aug 15;576:120426. doi: 10.1016/j.cca.2025.120426. Epub 2025 Jun 16.
Primary congenital hypothyroidism (CH) was classified into thyroid dysgenesis(TD) and thyroid dyshormonogenesis(TDH) based on pathophysiology, and into permanent CH (PCH) and transient CH (TCH) based on outcomes after age two. Despite progress in identifying pathogenic genes and genetic variants, the genetic characteristics and genotype-phenotype correlations remained insufficiently explored. This study aimed to identify novel variants, assess their pathogenicity, and analyze the correlation between genotype and phenotype.
Clinical data from 97 pediatric patients with primary CH were collected (32 previously reported, 65 newly diagnosed). Next-generation sequencing was used to screen for variants, and statistical analysis was performed on the clinical data.
Genetic etiologies were identified in 48% of patients, with 91% associated with TDH and 9% with TD. Six genes were involved: DUOX2 (68%), DUOXA2 (9%), TPO (9%), TG (6%), PAX8 (6%), and TSHR (2%). Seven novel variants were identified, including two pathogenic and five likely pathogenic. The TD-positive rate was significantly higher in the PCH group (43%) compared to the TCH group (0%). Genotype-phenotype analysis revealed that, at diagnosis, free thyroxine (FT4) levels were significantly lower in the genetic CH group compared to the carrier and wild-type groups. Additionally, the DUOX2 group had significantly higher free triiodothyronine (FT3) and FT4 levels at diagnosis compared to the non-DUOX2 group.
This study highlighted the significant role of genetic factors in primary CH, with DUOX2 being the most common pathogenic gene. Seven novel variants were identified, expanding the genetic spectrum. TDH might have been the main pathogenic mechanism, and TD was closely linked to PCH. Genetic CH was associated with lower FT4 levels, while DUOX2 variants correlated with milder biochemical phenotypes, further supporting genotype-phenotype correlations.
原发性先天性甲状腺功能减退症（CH）根据病理生理学分为甲状腺发育不全（TD）和甲状腺激素合成障碍（TDH），根据两岁后的结局分为永久性CH（PCH）和暂时性CH（TCH）。尽管在鉴定致病基因和遗传变异方面取得了进展，但遗传特征和基因型-表型相关性仍未得到充分探索。本研究旨在鉴定新的变异，评估其致病性，并分析基因型与表型之间的相关性。
收集97例小儿原发性CH患者的临床资料（32例既往报道，65例新诊断）。采用二代测序技术筛选变异，并对临床资料进行统计分析。
48%的患者确定了遗传病因，其中91%与TDH相关，9%与TD相关。涉及六个基因：DUOX2（68%）、DUOXA2（9%）、TPO（9%）、TG（6%）、PAX8（6%）和TSHR（2%）。鉴定出七个新变异，包括两个致病性变异和五个可能致病性变异。PCH组的TD阳性率（43%）显著高于TCH组（0%）。基因型-表型分析显示，在诊断时，遗传CH组的游离甲状腺素（FT4）水平显著低于携带者组和野生型组。此外，与非DUOX2组相比，DUOX2组在诊断时的游离三碘甲状腺原氨酸（FT3）和FT4水平显著更高。
本研究强调了遗传因素在原发性CH中的重要作用，其中DUOX2是最常见的致病基因。鉴定出七个新变异，扩大了遗传谱。TDH可能是主要致病机制，TD与PCH密切相关。遗传性CH与较低的FT4水平相关，而DUOX2变异与较轻的生化表型相关，进一步支持了基因型-表型相关性。
