Abstract
Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental genetic disorder, remaining under-diagnosed due to similarities with other known genetic syndromes. It is mainly characterized by severe intellectual disability, overbreathing, a typical facial gestalt, tendency to epilepsy and is caused by TCF4 haploinsufficiency. We report on a 14-year old boy, born to healthy non-consanguineous parents, with a PTHS spectrum phenotype, presenting with moderate to severe developmental delay, severe speech delay and facial dysmorphism. Genetic investigation using array-based comparative genomic hybridization (array-CGH) with a 400K custom array, revealed a 263.4 kb deletion within the TCF4 gene, removing exons 4-9. Parental array-CGH analysis was also performed, indicating paternal mosaicism for the same deletion. The mosaicism was confirmed by Quantitative Real-Time PCR. The current report describes a new TCF4 deletion associated with a PTHS phenotype. Moreover, it is the first case to our knowledge, where such a deletion is shown to be inherited from a clinically unaffected mosaic parent. Our results highlight the importance of parental testing in this setting for more accurate and focused prenatal diagnosis. The level and tissue-specificity of mosaicism in the father would be an interesting direction for further studies.