Fu Chunyun, Luo Jingsi, Su Jiasun, Zhang Shujie, Yang Qi, Zhang Yue
Medical Science Laboratory, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530003, People's Republic of China.
Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530003, People's Republic of China.
Int J Gen Med. 2023 Aug 8;16:3355-3362. doi: 10.2147/IJGM.S421382. eCollection 2023.
Congenital central hypothyroidism (CCH) is a rare disorder poorly described in childhood and adolescence. The current knowledge on the genetic bases of CCH is scarce. The purpose of this study was to analyze the clinical characteristics and molecular genetic basis of CCH in children.
We conducted a thorough evaluation of the clinical features in children diagnosed with CCH. Genomic DNA was extracted from peripheral blood of both children and their parents, and chromosomal microarray analysis and whole-exome sequencing were performed. Candidates for single nucleotide variants were validated using Sanger sequencing and were classified according to the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines.
Two cases with likely pathogenic variants were detected by whole-exome sequencing. Individual 1 carried a novel homozygous c.1418C>T (p.Ser473Phe) variant and a novel heterozygous c.416G>A. (p.Arg139Gln) variant. Individual 2 had a novel homozygous c.212C>T (p.Ala71Val) variant. The chromosomal microarray detected the presence of a 24 Mb heterozygous deletion (LOH: loss of heterozygosity) in the p12.1p13.13 region of chromosome 2 in individual 3, and the copy number variant was unknown of clinical significance.
Our study employed chromosomal microarray and whole-exome sequencing to investigate central hypothyroidism in seven children, leading to the detection of genetic anomalies in three individuals. The identification of novel variants has contributed to the expanded genetic spectrum of POU1F1 and ATP6V0A4 associated with pediatric central hypothyroidism.
先天性中枢性甲状腺功能减退症（CCH）是一种在儿童和青少年中描述较少的罕见疾病。目前关于CCH遗传基础的知识匮乏。本研究的目的是分析儿童CCH的临床特征和分子遗传基础。
我们对诊断为CCH的儿童的临床特征进行了全面评估。从儿童及其父母的外周血中提取基因组DNA，并进行染色体微阵列分析和全外显子测序。使用Sanger测序对单核苷酸变异的候选者进行验证，并根据美国医学遗传学与基因组学学会（ACMG）和分子病理学协会（AMP）的指南进行分类。
通过全外显子测序检测到2例可能的致病变异。个体1携带一个新的纯合c.1418C>T（p.Ser473Phe）变异和一个新的杂合c.416G>A.（p.Arg139Gln）变异。个体2有一个新的纯合c.212C>T（p.Ala71Val）变异。染色体微阵列检测到个体3的2号染色体p12.1p13.13区域存在一个24 Mb的杂合缺失（杂合性缺失：LOH），且该拷贝数变异的临床意义未知。
我们的研究采用染色体微阵列和全外显子测序对7名儿童的中枢性甲状腺功能减退症进行了研究，在3名个体中检测到了基因异常。新变异的鉴定扩展了与小儿中枢性甲状腺功能减退症相关的POU1F1和ATP6V0A4的遗传谱。
