JAG1 Variants Confer Genetic Susceptibility to Thyroid Dysgenesis and Thyroid Dyshormonogenesis in 813 Congenital Hypothyroidism in China

Abstract

Background and objective: Congenital hypothyroidism (CH) is indeed a prevalent neonatal endocrine disorder, affecting approximately 1 in 2000-3000 newborns worldwide, and 1 in 2400 newborns in China. Despite its high incidence, the genetic causes of CH, particularly those related to thyroid dysgenesis (TD), are still not well understood. However, previous studies have suggested that JAG1 may be a potential 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. The pathogenicity of the variants was assessed by bioinformatics softwares, protein sequence conservation analysis, and hydrophobic analysis. Further genetic analysis was conducted targeting 20 CH-related genes in these 25 JAG1 variant carriers.

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 a shared genetic factor in TD and DH, with a detection rate of 3.08% in Chinese individuals with CH. A comparison between the oligogenic and monogenic groups suggests a gene dosage effect in CH. Patients with the same JAG1 mutation exhibit diverse clinical phenotypes, indicating complex mechanisms underlying phenotypic heterogeneity.

Keywords: JAG1; congenital hypothyroidism; inheritance model; pathogenic variant; phenotypic heterogeneity.

Figure 1

Multiple sequences alignment. Multiple sequences alignment were conducted using ClustalW2 among Homo sapiens, Mus musculus, Rattus norvegicus, Sus scrofa, Pan troglodytes, Bos Taurus, Macaca mulatta and Felis catus. (A) Multiple sequences alignment of JAG1; (B) Multiple sequences alignment of DUOX2; (C) Multiple sequences alignment of DUOXA2. The mutation sites were marked by red arrows.

Figure 2

The changes of hydrophobic parameters caused by amino acid substitution. Wild-type amino acids were marked with black, substituted amino acids were marked with red; “+” means increased hydrophobicity, “-” means decreased hydrophobicity.

Figure 3

Analysis of genotype and phenotype relationship (A) The distribution of the number of variants carried by each patients; (B) The comparison of fT4 concentration between monogenic group and oligogenic group; (C) The comparison of fT4 concentration between monogenic DH and oligogenic DH; (D) The comparison of fT4 concentration between monogenic TD and monogenic DH. “ns” means P>0.05, “*” means P<0.05.

Figure 4

Clustering analysis of JAG1 variants in CH. Distance in nucleotides between missense mutations within exons 1–21 and exons 22–26. Statistical significance was calculated using an unpaired, two-tailed t test, “*” means P<0.05.