Genetic Heterogeneity in Susceptibility to Familial Thyroid Nodular Disease
Authors' conclusion
This study highlights the substantial genetic heterogeneity underlying familial TFND. While most kindreds lacked clear monogenic causes, DICER1 explained familial disease in one pedigree, whereas the SLC26A4 findings supported a likely somatic second-hit mechanism in a single affected member of another pedigree without accounting for the familial aggregation.
Study context
- Population
- Affected individuals from eight pedigrees with familial euthyroid thyroid follicular nodular disease (TFND; formerly nontoxic multinodular goiter), including pedigrees suggestive of autosomal dominant inheritance8 pedigrees
- Participants
- 28 individuals
- Outcome
- Rare germline genetic variants contributing to familial euthyroid TFND
Methodological detailswhole-exome sequencing of familial pedigrees, cross-pedigree and kindred-based analyses, somatic sequencing of TFND tissues, Somatic sequencing of four available TFND tissues for second-hit mechanisms or copy number alterations (CNA)
- Whole-exome sequencing of familial pedigrees
- Cross-pedigree and kindred-based analyses
- Somatic sequencing of TFND tissues
- Somatic sequencing of four available TFND tissues for second-hit mechanisms or CNA
Main finding
As reported in the abstract
Rare germline variants
- Cross-pedigree analysis: one gene with variants of uncertain significance, not definitive candidates
- Truncating DICER1 variant in a kindred previously linked to the MNG-1 locus, associated with early disease onset
- Heterozygous SLC26A4 variant in one affected individual of another kindred, with loss of heterozygosity in the patient's tissue
- Pathogenic WFS1 variant in one kindred, supporting a candidate-gene role but requiring further validation
- Germline CNA analysis and targeted PLCB1 screening in all kindreds negative
Original publication
Genetic Heterogeneity in Susceptibility to Familial Thyroid Nodular Disease. Thyroid. Published 11 September 2026. doi:10.
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