Stoupa Athanasia, Kariyawasam Dulanjalee, Jabot-Hanin Fabienne, Nguyen-Quoc Adrien, Hanein Sylvain, Rabeony Tioka, Elie Caroline, Colas Sandra, Thalassinos Caroline, Oliver-Petit Isabelle, Houang Muriel, Coutant Régis, Barat Pascal, Nicolino Marc, Reynaud Rachel, de Kerdanet Marc, Bensignor Candace, Baron Sabine, Raynaud-Ravni Catherine, Souchon Pierre-François, Léger Juliane, Castanet Mireille, Bole-Feysot Christine, Nitschke Patrick, Lyonnet Stanislas, Polak Michel, Carré Aurore
Pediatric Endocrinology, Gynecology and Diabetology Department, Necker Children's University Hospital, Assistance Publique Hôpitaux de Paris (APHP), 75015 Paris, France.
Paris Regional Newborn Screening Program, Centre Régional de Dépistage Néonatal (CRDN) Ile de France, 75015 Paris, France.
J Clin Endocrinol Metab. 2025 Sep 16;110(10):e3489-e3502. doi: 10.1210/clinem/dgaf004.
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.
Gain insight into the inheritance mode of CHTD.
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.
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.
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.
先天性甲状腺功能减退症（CH）是最常见的新生儿内分泌疾病，主要由甲状腺发育不全（CHTD）引起。该病的遗传模式仍然复杂。
深入了解CHTD的遗传模式。
在法国进行的一项前瞻性多中心全国性转化研究，纳入了514例通过新生儿系统筛查确诊的CH患者（HYPOTYGEN队列）。我们聚焦于CHTD病例，研究其临床和分子表型。使用包含78个基因的基因panel进行靶向二代测序，这些基因涉及甲状腺发育、功能、转运、甲状腺激素代谢及作用。进行了统计分析、家系分离分析以及聚焦细胞迁移的体外功能研究。
我们分析了458例CH患者的临床表型。心脏和肾脏畸形分别出现在7.7%（14/182）和3.9%（7/178）的患者中。基于种族标准以及索引病例及其父母的DNA样本可用性，对队列中的292例患者进行了基因分析。在20/292（6.8%）的患者中鉴定出10个已知CHTD相关基因中的1个致病突变。我们在16例（5.5%）患者中发现了双基因遗传模式，每例患者在一个甲状腺发育基因和H2O2生成复合体基因DUOX2/DUOXA2中各携带一个变异。家系分离分析和体外功能研究支持了该模型。
这项工作通过证明双基因遗传可能与甲状腺发育及DUOX2/DUOXA2基因中的有害变异有关，扩展了我们对CHTD分子病因的理解。这种模式的复杂性意味着需要修订CHTD的遗传图谱，并在长期随访中对患者进行特定的临床护理。
