JAG1 Variants Confer Genetic Susceptibility to Thyroid Dysgenesis and Thyroid Dyshormonogenesis with Different Mechanisms

Abstract Background and objective: Congenital hypothyroidism (CH) is the most common and preventable neonatal endocrine disorder, with an incidence of 1 in 2000–3000 newborns worldwide, and 1 in 2400 in China. However, the genetic causes of congenital hypothyroidism, in particular due to thyroid dysgenesis (TD) remain largely unknown. Previous study indicated that JAG1 is a novel susceptibility gene for congenital thyroid defects. To explore the association between JAG1 and CH, we screened JAG1 variants in a large cohort of 813 CH patients. Methods We performed genetic analysis of JAG1 using next-generation sequencing in 813 CH cases. After data analysis and verification by Sanger sequencing, we identified 10 pathogenic variants in 25 patients. And then we performed further genetic analysis targeting 20 CH related genes in these 25 JAG1 variant carriers. The pathogenicity of variants were assessed by bioinformatics softwares, protein sequence conservation analysis, and hydrophobic analysis. Results We identified 10 pathogenic missense mutations (p.V45L, p.V272I, p.P552L, p.G610E, p.G852D, p.A891T, p.E1030K, p.R1060W, p.A1131T, p.P1174L) carried by 25 patients, the mutation rate of JAG1 in CH was 3.08%. Among these 25 patients, 16 with 1 variant, 6 with 2 variants, and the other 3 with 3 variants. Our findings indicated that JAG1 variants confer genetic susceptibility to both TD and DH, but with different inheritance models. JAG1 variants lead to TD mainly through monogenic model, while for DH cases, both monogenic mechanisms and oligogenic mechanisms play a pivotal role. Oligogenicity may contribute to the disease severity of DH. Conclusion JAG1 is one of the overlap of genetic aetiologies in TD and DH, with the detection rate in CH in China was 3.08%. The comparation between oligogenic group and monogenic group revealed that CH may exhibit a gene dosage effect. Patients with the same JAG1 mutation demonstrate a broad spectrum of clinical phenotypes, indicating the mechanisms involved in its phenotypic heterogeneity is complex.