Maternal isodisomy for chromosome 9 causing homozygosity for a novel FOXE1 mutation in syndromic congenital hypothyroidism

Context: Homozygous loss-of-function mutations in forkhead box E1/thyroid transcription factor 2 (FOXE1/TTF-2) cause syndromic congenital hypothyroidism, with thyroid dysgenesis, cleft palate, spiky hair, and variable choanal atresia and bifid epiglottis in three cases reported hitherto. We have elucidated the molecular basis of the disorder in a female with a similar clinical phenotype, born to nonconsanguineous parents. Objective and Design: The FOXE1 gene, located on chromosome 9q22, was sequenced in the proband and family members. Microsatellite marker and multiplex ligation probe amplification analyses determined chromosomal inheritance patterns and FOXE1 copy number. Mutant FOXE1 function was predicted by structural modeling and tested in transfection assays. Results: The proband was homozygous for a novel missense (c.412T→C; F137S) FOXE1 mutation, but her mother showed heterozygous and father wild-type alleles for this gene sequence. However, the proband was also homozygous for 10 microsatellite markers spanning chromosome 9 with exclusively maternal inheritance. Multiplex ligation probe amplification assays showed two copies of FOXE1 in the proband, indicating maternal isodisomy for chromosome 9. Consistent with structural modeling, the F137S mutant FOXE1 protein failed to bind DNA and showed negligible transcriptional activity. Conclusion: We have described the first case of uniparental disomy causing homozygosity for a novel, loss-of-function FOXE1/TTF-2 mutation in dysgenetic congenital hypothyroidism.