PAX8 pathogenic variants in Chinese patients with congenital hypothyroidism

• We conducted the largest PAX8 gene mutation screening so far in CH patients.
• We identified PAX8 pathogenic variants in 9 of 378 cases (2.38%).
• Most of the patients with PAX8 pathogenic variants were associated with permanent CH.
• We reported three novel pathogenic variants.
• Our study provided the best estimation of mutation rate for CH patients in Guangxi, China.

BackgroundThe clinical presentation of patients with congenital hypothyroidism (CH) caused by paired box gene 8 (PAX8) pathogenic variants is variable and PAX8 mutation rates differ significantly among different populations. This study was set to examine the PAX8 mutation spectrum and prevalence among patients with CH in Guangxi Zhuang Autonomous Region, China.MethodsPeripheral venous blood samples were collected from the patients. Genomic DNA was extracted from peripheral blood leukocytes. All exons of the 11 known CH associated genes including PAX8 together with their exon–intron boundaries were screened by next-generation sequencing (NGS). Permanent or transient CH was determined using the results of thyroid function tests after temporary withdrawal of l-thyroxine (l-T4) therapy at approximately 2 years of age.ResultsNext generation sequencing analysis of PAX8 in 378 CH patients revealed five different mutations in nine individuals (two are siblings). The mutations included two known missense variants, namely c.92G > A (p.R31H) and c.91C > T (p.R31C), and one novel missense variant c.68G > T (p.G23V), as well as two novel nonsense variants c.1090C > T (p. R364X) and c.658C > T (p.R220X). The variant c.92G > A (p.R31H) is highly recurrent in our patient cohort but the clinical phenotypes vary greatly among those carrying this variant. PAX8 pathogenic variants were mainly associated with permanent CH.ConclusionThe prevalence of PAX8 pathogenic variants was 2.38% among patients with CH in Guangxi. Our study expanded the PAX8 mutation spectrum and provided the best estimation of PAX8 mutation rate among CH patients in Guangxi, China.