Dataset Information

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.

SUBMITTER: Li M

PROVIDER: S-EPMC10926855 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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<i>JAG1</i> Variants Confer Genetic Susceptibility to Thyroid Dysgenesis and Thyroid Dyshormonogenesis in 813 Congenital Hypothyroidism in China.

Li Miaomiao M Wang Xiaoyu X Wang Fang F Wang Fengqi F Zhao Dehua D Liu Shiguo S

International journal of general medicine 20240307

<h4>Background and objective</h4>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 betw ...[more]

PMID: 38468821

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Project description:Context: Congenital hypothyroidism due to thyroid dysgenesis (CHTD) is a predominantly sporadic and nonsyndromic (NS) condition of unknown etiology. NS-CHTD shows a 40-fold increase in relative risk among first-degree relatives (1 in 100 compared with a birth prevalence of 1 in 4000 in the general population), but a discordance rate between monozygotic (MZ) twins of 92%. This suggests a two-hit mechanism, combining a genetic predisposition (incomplete penetrance of inherited variants) with postzygotic events (accounting for MZ twin discordance). Objective: To evaluate whether whole-exome sequencing (WES) allows to identify new predisposing genes in NS-CHTD. Methods: We performed a case-control study by comparing the whole exome of 36 nonconsanguineous cases of NS-CHTD (33 with lingual thyroid ectopy and 3 with athyreosis, based on technetium pertechnetate scintigraphy at diagnosis) with that of 301 unaffected controls to assess for enrichment in rare protein-altering variants. We performed an unbiased approach using a gene-based burden with a false discovery rate correction. Moreover, we identified all rare pathogenic and likely pathogenic variants, based on in silico prediction tools, in 27 genes previously associated with congenital hypothyroidism (CH) (thyroid dysgenesis [TD] and dyshormonogenesis). Results: After correction for multiple testing, no enrichment in rare protein-altering variants was observed in NS-CHTD. Pathogenic or likely pathogenic variants (21 variants in 12 CH genes) were identified in 42% of cases. Eight percent of cases had variants in more than one gene (oligogenic group); these were not more severely affected than monogenic cases. Moreover, cases with protein-altering variants in dyshormonogenesis-related genes were not more severely affected than those without. Conclusions: No new predisposing genes were identified following an unbiased analysis of WES data in a well-characterized NS-CHTD cohort. Nonetheless, the discovery rate of rare pathogenic or likely pathogenic variants was 42%. Eight percent of the cases harbored multiple variants in genes associated with TD or dyshormonogenesis, but these variants did not explain the variability of hypothyroidism observed in dysgenesis. WES did not identify a genetic cause in NS-CHTD cases, confirming the complex etiology of this disease. Additional studies in larger cohorts and/or novel discovery approaches are required.