Genetic Basis of Congenital Central Hypothyroidism in Children: Expanding the Mutational Spectrum of POU1F1 and ATP6V0A4

OBJECTIVE: 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. METHODS: 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. RESULTS: Two cases with likely pathogenic variants were detected by whole-exome sequencing. Individual 1 carried a novel homozygous ATP6V0A4 c.1418C>T (p.Ser473Phe) variant and a novel heterozygous POU1F1 c.416G>A. (p.Arg139Gln) variant. Individual 2 had a novel homozygous POU1F1 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. CONCLUSION: 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.