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

Summary

In a nationwide prospective cohort with targeted sequencing and functional validation, 5.5% of thyroid dysgenesis cases exhibited digenic inheritance involving a thyroid development gene and DUOX2/DUOXA2, supported by segregation and in vitro assays. These findings redefine the genetic architecture of congenital hypothyroidism due to dysgenesis and argue for broader genetic testing and tailored follow-up.

Key Findings

• Among 292 genotyped patients, 6.8% carried a pathogenic variant in one of 10 known CHTD genes.
• Digenic inheritance was identified in 16 patients (5.5%), combining a thyroid development gene variant with a DUOX2/DUOXA2 variant.
• Segregation analysis and in vitro functional studies supported the digenic model; cardiac (7.7%) and renal (3.9%) malformations were noted.

Clinical Implications

Expand genetic testing to include combined assessment of thyroid development genes with DUOX2/DUOXA2; counsel families on digenic risk; plan long-term endocrine follow-up acknowledging syndromic malformation rates.

Limitations

• Genetic analysis performed in a subset (292/514) based on DNA availability and criteria, potentially introducing selection bias
• Targeted panel limits discovery of variants outside the 78 genes; functional studies focused on select pathways

Future Directions

Adopt exome/genome-wide approaches to capture additional digenic/oligogenic architectures; establish penetrance estimates and clinical algorithms integrating genotype for surveillance.