Digenic Inheritance Mode in Congenital Hypothyroidism Due to Thyroid Dysgenesis: HYPOTYGEN Translational Cohort Study

Athanasia Stoupa^{1

2

3

4}, Dulanjalee Kariyawasam^{1

3

4

5}, Fabienne Jabot-Hanin⁶, Adrien Nguyen-Quoc⁴, Sylvain Hanein⁶, Tioka Rabeony⁷, Caroline Elie⁷, Sandra Colas⁷, Caroline Thalassinos¹, Isabelle Oliver-Petit⁸, Muriel Houang⁹, Régis Coutant¹⁰, Pascal Barat¹¹, Marc Nicolino¹², Rachel Reynaud¹³, Marc de Kerdanet¹⁴, Candace Bensignor¹⁵, Sabine Baron¹⁶, Catherine Raynaud-Ravni¹⁷, Pierre-François Souchon¹⁸, Juliane Léger¹⁹, Mireille Castanet²⁰, Christine Bole-Feysot²¹, Patrick Nitschke⁶, Stanislas Lyonnet^{22

23}, Michel Polak^{1

2

3

4

5

24}, Aurore Carré^{3

4}

Affiliations

¹ Pediatric Endocrinology, Gynecology and Diabetology Department, Necker Children's University Hospital, Assistance Publique Hôpitaux de Paris (APHP), 75015 Paris, France.
² Paris Regional Newborn Screening Program, Centre Régional de Dépistage Néonatal (CRDN) Ile de France, 75015 Paris, France.
³ INSERM U1163, IMAGINE Institute Affiliate, 75015 Paris, France.
⁴ INSERM U1016, Cochin Institute, 75014 Paris, France.
⁵ Faculté de Médecine, Université Paris Cité, 75006 Paris, France.
⁶ Bioinformatics Platform, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS 3633, IMAGINE Institute, Université Paris Cité, 75015 Paris, France.
⁷ Clinical Research Unit/Clinical Investigation Center, APHP, Necker Children's University Hospital, 75015 Paris, France.
⁸ Endocrinology, Gynecology and Bone Disease Department, Children's University Hospital, 31000 Toulouse, France.
⁹ Pediatric Endocrinology Department, Armand Trousseau Hospital, 75012 Paris, France.
¹⁰ Pediatrics Department, CHU Angers, 49000 Angers, France.
¹¹ Pediatric Endocrinology Unit, Bordeaux University Hospital, 33000 Bordeaux, France.
¹² Pediatrics Department, CHU de Lyon, 69000 Lyon, France.
¹³ Pediatrics Department, CHU Timone, 13005 Marseille, France.
¹⁴ Pediatrics Department, CHU Rennes, 35033 Rennes, France.
¹⁵ Pediatrics Department, University Hospital, 21000 Dijon, France.
¹⁶ Pediatrics Department, Hôpital Femme Enfant Adolescent, CHU Nantes, 44000 Nantes, France.
¹⁷ Pediatrics Department, CHU Saint Etienne, 42055 Saint Etienne, France.
¹⁸ American Memorial Hospital, Pediatrics Department, CHU Reims, 51100 Reims, France.
¹⁹ Department of Pediatric Endocrinology and Diabetes, Reference Center for Rare Endocrine Growth and Development Diseases, APHP, Robert Debré University Hospital, University of Paris, NeuroDiderot Institut National de la Santé et de la Recherche Médicale (INSERM), 75019 Paris, France.
²⁰ Normandie University, UNIROUEN, CHU Rouen, Medical Pediatrics Department, and CIC-CRB 1404, 76031 Rouen, France.
²¹ Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 & INSERM US24/CNRS UAR3633, Paris Cite University, 75015 Paris, France.
²² Université Paris Cité, INSERM, IHU IMAGINE-Institut des Maladies Génétiques, Laboratoire Embryologie et Génétique des Malformations, 75015 Paris, France.
²³ Service de Médecine Génomique des Maladies Rares, Necker Children's University Hospital, APHP, 75015 Paris, France.
²⁴ Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du Développement, Necker Children's University Hospital, APHP, 75015 Paris, France.

PMID: 39787321
DOI: 10.1210/clinem/dgaf004

Multicenter Study

Digenic Inheritance Mode in Congenital Hypothyroidism Due to Thyroid Dysgenesis: HYPOTYGEN Translational Cohort Study

Athanasia Stoupa et al. J Clin Endocrinol Metab. 2025.

. 2025 Sep 16;110(10):e3489-e3502.

doi: 10.1210/clinem/dgaf004.

Authors

Affiliations

¹ Pediatric Endocrinology, Gynecology and Diabetology Department, Necker Children's University Hospital, Assistance Publique Hôpitaux de Paris (APHP), 75015 Paris, France.
² Paris Regional Newborn Screening Program, Centre Régional de Dépistage Néonatal (CRDN) Ile de France, 75015 Paris, France.
³ INSERM U1163, IMAGINE Institute Affiliate, 75015 Paris, France.
⁴ INSERM U1016, Cochin Institute, 75014 Paris, France.
⁵ Faculté de Médecine, Université Paris Cité, 75006 Paris, France.
⁶ Bioinformatics Platform, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS 3633, IMAGINE Institute, Université Paris Cité, 75015 Paris, France.
⁷ Clinical Research Unit/Clinical Investigation Center, APHP, Necker Children's University Hospital, 75015 Paris, France.
⁸ Endocrinology, Gynecology and Bone Disease Department, Children's University Hospital, 31000 Toulouse, France.
⁹ Pediatric Endocrinology Department, Armand Trousseau Hospital, 75012 Paris, France.
¹⁰ Pediatrics Department, CHU Angers, 49000 Angers, France.
¹¹ Pediatric Endocrinology Unit, Bordeaux University Hospital, 33000 Bordeaux, France.
¹² Pediatrics Department, CHU de Lyon, 69000 Lyon, France.
¹³ Pediatrics Department, CHU Timone, 13005 Marseille, France.
¹⁴ Pediatrics Department, CHU Rennes, 35033 Rennes, France.
¹⁵ Pediatrics Department, University Hospital, 21000 Dijon, France.
¹⁶ Pediatrics Department, Hôpital Femme Enfant Adolescent, CHU Nantes, 44000 Nantes, France.
¹⁷ Pediatrics Department, CHU Saint Etienne, 42055 Saint Etienne, France.
¹⁸ American Memorial Hospital, Pediatrics Department, CHU Reims, 51100 Reims, France.
¹⁹ Department of Pediatric Endocrinology and Diabetes, Reference Center for Rare Endocrine Growth and Development Diseases, APHP, Robert Debré University Hospital, University of Paris, NeuroDiderot Institut National de la Santé et de la Recherche Médicale (INSERM), 75019 Paris, France.
²⁰ Normandie University, UNIROUEN, CHU Rouen, Medical Pediatrics Department, and CIC-CRB 1404, 76031 Rouen, France.
²¹ Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 & INSERM US24/CNRS UAR3633, Paris Cite University, 75015 Paris, France.
²² Université Paris Cité, INSERM, IHU IMAGINE-Institut des Maladies Génétiques, Laboratoire Embryologie et Génétique des Malformations, 75015 Paris, France.
²³ Service de Médecine Génomique des Maladies Rares, Necker Children's University Hospital, APHP, 75015 Paris, France.
²⁴ Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du Développement, Necker Children's University Hospital, APHP, 75015 Paris, France.

PMID: 39787321
DOI: 10.1210/clinem/dgaf004

Abstract

Context: Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and is chiefly caused by thyroid dysgenesis (CHTD). The inheritance mode of the disease remains complex.

Objective: Gain insight into the inheritance mode of CHTD.

Methods: Prospective multicenter nationwide translational study in France including 514 patients with CH diagnosed through systematic newborn screening (HYPOTYGEN cohort). We focused on CHTD cases and studied their clinical and molecular phenotypes. Targeted next-generation sequencing using a 78-gene panel, including genes involved in thyroid development, function, transport, metabolism and action of thyroid hormones. Statistical analysis, familial segregation, and in vitro functional studies focusing on cell migration have been performed.

Results: We analyzed the clinical phenotypes of 458 patients with CH. Cardiac and renal malformations were present in 7.7% (14/182) and 3.9% (7/178) of patients, respectively. Genetic analysis was performed on 292 patients of the cohort, based on criteria for ethnicity and availability of DNA samples for index cases and their parents. A disease-causing mutation in 1 of the 10 known genes for CHTD was identified in 20/292 (6.8%) patients. We found a digenic mode of inheritance in 16 (5.5%) patients, each carrying a variant in a thyroid development gene and a variant in the H2O2 generation complex gene DUOX2/DUOXA2. Familial segregation analysis and in vitro functional studies supported this model.

Conclusion: This work expands our understanding of the molecular causes of CHTD by demonstrating that digenic inheritance can be implicated, with deleterious variants in thyroid development and DUOX2/DUOXA2 genes. The complexity of this model implies a revision of the genetic landscape of CHTD and specific clinical care of patients during long-term follow-up.

Keywords: DUOX2/DUOXA2; congenital hypothyroidism; digenism; genetic model; genomics; targeted-NGS; thyroid dysgenesis.

© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.

PubMed Disclaimer

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Digenic Inheritance Mode in Congenital Hypothyroidism Due to Thyroid Dysgenesis: HYPOTYGEN Translational Cohort Study

Affiliations

Digenic Inheritance Mode in Congenital Hypothyroidism Due to Thyroid Dysgenesis: HYPOTYGEN Translational Cohort Study

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources