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Although familial aggregation and genetic predisposition have been observed, the underlying molecular mechanisms remain only partially defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective:<\/jats:title>\n                    <jats:p>To identify rare germline genetic variants contributing to familial euthyroid TFND, including families with pedigrees suggestive of autosomal dominant inheritance, using whole-exome sequencing (WES).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>WES was performed on germline DNA from 28 affected individuals belonging to eight pedigrees exhibiting TFND. Two analytical approaches were applied, including a cross-pedigree analysis to detect disrupted genes shared across multiple kindreds and kindred-based analyses to identify rare pathogenic variants segregating within individual pedigrees or single affected individuals. Somatic sequencing of four available TFND tissues was also performed to search for second-hit mechanisms or copy number alterations (CNA).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Cross-pedigree analysis identified one gene carrying variants of uncertain significance, which did not emerge as definitive candidates. Pedigree-specific analyses revealed a truncating\n                      <jats:italic toggle=\"yes\">DICER1<\/jats:italic>\n                      variant in a kindred previously linked to the MNG-1 locus and associated with early disease onset; a heterozygous\n                      <jats:italic toggle=\"yes\">SLC26A4<\/jats:italic>\n                      variant in only one affected individual from another kindred and loss of heterozygosity in the patient\u2019s tissue; and a pathogenic\n                      <jats:italic toggle=\"yes\">WFS1<\/jats:italic>\n                      variant in one kindred, supporting its previously proposed role as a TFND candidate gene, but requiring further validation. Both germline CNA analysis and targeted\n                      <jats:italic toggle=\"yes\">PLCB1<\/jats:italic>\n                      screening in all kindreds yielded negative results.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      This study highlights the substantial genetic heterogeneity underlying familial TFND. While most kindreds lacked clear monogenic causes,\n                      <jats:italic toggle=\"yes\">DICER1<\/jats:italic>\n                      explained familial disease in one pedigree, whereas the\n                      <jats:italic toggle=\"yes\">SLC26A4<\/jats:italic>\n                      findings supported a likely somatic second-hit mechanism in a single affected member of another pedigree without accounting for the familial aggregation. The findings support a multifactorial etiology and suggest that TFND represents a phenotypic manifestation within broader hereditary syndromes. Integrating family-based sequencing with functional validation will be critical to fully delineate pathogenic mechanisms and broaden the spectrum of genes implicated in thyroid nodular disease.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/10507256261485457","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T07:24:01Z","timestamp":1789111441000},"page":"1190-1202","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Heterogeneity in Susceptibility to Familial Thyroid Nodular Disease"],"prefix":"10.1177","volume":"36","author":[{"given":"Anne-Sophie","family":"Chong","sequence":"first","affiliation":[{"name":"Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), Bellvitge Biomedical Research Institute (IDIBELL), L\u2019Hospitalet de Llobregat, Barcelona, Spain."},{"name":"Genetics Program, Faculty of Biology, University of Barcelona, Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Paschke","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabet","family":"Munt\u00e9","sequence":"additional","affiliation":[{"name":"Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), Bellvitge Biomedical Research Institute (IDIBELL), L\u2019Hospitalet de Llobregat, Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Rioja","sequence":"additional","affiliation":[{"name":"Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), Bellvitge Biomedical Research Institute (IDIBELL), L\u2019Hospitalet de Llobregat, Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilian","family":"Bomme Ousager","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Odense University Hospital, Odense, Denmark."},{"name":"Department of Clinical Research, University of Southern Denmark, Odense, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne Marie","family":"Jelsig","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"D\u00e9sir","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, The Centre Hospitalier Universitaire Brugmann, Brussels, Belgium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William D.","family":"Foulkes","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, McGill University, Montreal, Quebec, Canada."},{"name":"Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9434-6288","authenticated-orcid":false,"given":"Barbara","family":"Rivera","sequence":"additional","affiliation":[{"name":"Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), Bellvitge Biomedical Research Institute (IDIBELL), L\u2019Hospitalet de Llobregat, Barcelona, Spain."},{"name":"Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"e_1_3_3_2_1","volume-title":"WHO Classification of Endocrine and Neuroendocrine Tumors","author":"International Agency for Research on C, World Health O","year":"2025","unstructured":"1.International Agency for Research on C, World Health O. 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