Next-generation sequencing analysis of PAX8 gene variants in Chinese children with congenital hypothyroidism
10.3760/cma.j.cn311282-20250212-00065
- VernacularTitle:采用二代测序分析中国先天性甲状腺功能减退症患儿PAX8基因变异
- Author:
Chenyang WU
1
;
Huaidong SONG
1
;
Shuangxia ZHAO
1
Author Information
1. 上海交通大学医学院附属第九人民医院分子诊断科，中心实验室，内分泌代谢病科，上海交通大学组学与疾病全国重点实验室，上海 200001
- Publication Type:Journal Article
- Keywords:
Congenital hypothyroidism;
PAX8 gene;
Gene variant;
Autosomal dominant inheritance
- From:
Chinese Journal of Endocrinology and Metabolism
2025;41(6):453-459
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To conduct clinical analysis and genetic variant detection in patients with congenital hypothyroidism, and to explore the role of paired box 8(PAX8) gene variants in the pathogenic mechanism of congenital hypothyroidism, thereby providing insights for its diagnosis and management.Methods:This study was a retrospective analysis based on previously collected clinical and genetic data. Clinical information from 763 children with congenital hypothyroidism and some of their family members was collected between 2014 and 2025. Peripheral blood samples were obtained for genomic DNA extraction. Next-generation sequencing was performed to detect pathogenic variants in the patients. The identified pathogenic PAX8 variants were confirmed by Sanger sequencing and pedigree analysis. Functional analysis of the variant was then performed using bioinformatics tools.Results:Five PAX8 variants were identified among 763 children with congenital hypothyroidism. One proband was identified through neonatal screening and subsequently confirmed to have congenital hypothyroidism. Thyroid ultrasound revealed a small thyroid gland. A heterozygous missense variant in the PAX8 gene, NM_003466.3: c.91C>T: p.R31C, was identified in this proband, resulting in the substitution of arginine with cysteine at Codon 31 of the PAX8 protein. Sanger sequencing confirmed that this was a de novo variant, as it was absent in the proband′s parents. Multiple bioinformatic programs consistently predicted the variant to be deleterious. According to the American College of Medical Genetics and Genomics(ACMG) guidelines, the variant was classified as pathogenic. Conclusions:A de novo PAX8 variant, p. R31C, was identified in a patient with congenital hypothyroidism. This variant is located within the paired domain of the PAX8 protein and may impair the protein′s function by disrupting its binding to DNA.
