Deletion of Exon 1 of the SLC16A2 Gene: A Common Occurrence in Patients with Allan-Herndon-Dudley Syndrome

Background: Allan-Herndon-Dudley syndrome (AHDS) is an X-linked type of mental retardation resulting from hindered thyroid hormone access to neurons. Clustered nonrecurrent deletions of SLC16A2 exon 1 have been described in three patients with AHDS. We report a fourth patient with such a deletion and discuss possible mechanisms leading to these rearrangements. Case Presentation: A three-and-a-half-year-old male with clinical and biochemical AHDS phenotype and a history of normal neonatal screening for hypothyroidism underwent SLC16A2 molecular analysis. Unexpectedly, he showed skeletal signs of hypothyroidism. Methods and Results: The exons of the SLC16A2 (MCT8) gene and the sequences surrounding exon 1 were amplified using PCR. The patient had a 36-kb deletion affecting exon 1 of SLC16A2. The deletion junction was subjected to bioinformatic analyses, along with two other reported exon 1 deletion junctions, identifying possible sequence features and mechanisms responsible for such genomic rearrangements. Discussion/Conclusion: This patient had a classic AHDS phenotype with an unexpectedly large anterior fontanel and delayed bone age and dentition. Bioinformatic analyses suggested that exon 1 deletions in patients with AHDS are caused by microhomology-mediated replicative-based and nonhomologous end-joining mechanisms. Rearrangement susceptibility may be due to the size of intron 1 and the percentage of repeat sequences.