FOXE1 – Congenital hypothyroidism

Congenital hypothyroidism (CH) due to thyroid dysgenesis (TD) often presents with variable extra-thyroidal anomalies, including cleft palate and choanal atresia. FOXE1 encodes thyroid transcription factor 2 (TTF-2), a forkhead-domain protein essential for thyroid bud migration and palate fusion. The inheritance mode is autosomal recessive, with homozygous loss-of-function variants identified in syndromic CH cases associated with thyroid agenesis or gland in situ.

Three unrelated consanguineous families harboring distinct homozygous missense variants in the forkhead DNA-binding domain of FOXE1 have been reported. In two siblings with complete thyroid agenesis, cleft palate and choanal atresia, the c.194C>T (p.Ala65Val) variant was identified (2 probands) (PMID:9697705). In a second sibship with CH, athyreosis and cleft palate but no choanal atresia, c.170G>A (p.Ser57Asn) was found (2 probands) (PMID:12165566). A third case, a female with eutopic gland, cleft palate and bilateral choanal atresia, carried c.304C>T (p.Arg102Cys) (1 proband) (PMID:16882747). None of these variants were detected in ≥100 ethnically matched control chromosomes.

Functional assays demonstrate that all three forkhead-domain mutants abolish DNA binding and severely impair transcriptional activation of thyroid gene promoters, consistent with a loss-of-function mechanism. The phenotypic heterogeneity—absence of thyroid agenesis in the R102C case and variable presence of choanal atresia—correlates with residual transcriptional activity in vitro.

Further evidence from a large CH cohort (n=1752) identified a heterozygous c.319C>G (p.Leu107Val) variant in five siblings homozygous for a 14-alanine polyalanine tract; this variant reduces FOXE1 transcriptional synergy with partner factors and alters subcellular localization, implicating polyalanine tract length in thyroid dysgenesis susceptibility (PMID:37008944).

Collectively, these data support a Moderate ClinGen clinical validity classification for FOXE1 in syndromic CH: 5 affected individuals across 3 families with autosomal recessive segregation and concordant functional assays. Genetic testing for FOXE1 should be considered in CH patients with associated cleft palate and choanal atresia, even in the presence of eutopic thyroid tissue.

Key Take-home: Homozygous FOXE1 loss-of-function alleles cause a syndromic form of congenital hypothyroidism with or without thyroid agenesis, guiding targeted genetic diagnosis.

References

• Nature genetics • 1998 • Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia. PMID:9697705
• Human molecular genetics • 2002 • A novel loss-of-function mutation in TTF-2 is associated with congenital hypothyroidism, thyroid agenesis and cleft palate. PMID:12165566
• The Journal of clinical endocrinology and metabolism • 2006 • A novel missense mutation in human TTF-2 (FKHL15) gene associated with congenital hypothyroidism but not athyreosis. PMID:16882747
• Frontiers in endocrinology • 2023 • The length of FOXE1 polyalanine tract in congenital hypothyroidism: Evidence for a pathogenic role from familial, molecular and cohort studies. PMID:37008944

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