A new case of intragenic deletion of the TCF4 gene without features of Pitt-Hopkins syndrome

Different genomicalterations affecting the TCF4 gene are usually associated with Pitt-Hopkinssyndrome (PTHS). This syndrome is a rare neurodevelopmental genetic disordercharacterized by distinctive facial features, abnormal breathing, psychomotordelay and severe intellectual disability (ID). The genomic alterations includewhole or partial gene deletion; balanced translocation disrupting the codingsequence of the gene; and intragenic variants. The TCF4 gene encodes a basichelix-loop-helix (bHLH) transcription factor 4. Using alternative promoters,TCF4 can be transcribed from a number of alternative initial exons, allowingfor translation of variable protein isoforms containing different functionaldomains. Full-length TCF4 has two activation domains (AD1 and AD2) that arethought to modulate transcriptional activity, a NLS domain (nuclearlocalization signal) that controls subcellular localization and bHLH domain.Typical PTHS patients have aberration localized between exons 9 and 18 of thegene. On the other hand, variants affecting the first protein coding exons giverise to mild non-syndromic ID. We present a ten-year-old girl with psychomotordelay and mild ID without the typical features of PTHS. Genetic investigationusing array-based comparative genomic hybridization, revealed a 73.45 kbdeletion within the TCF4 gene. The deletion encompassing only exon 6(NM_001083962). This deletion was not detected in both parents. Cytogeneticanalysis excluded balanced translocation disrupting the coding sequence of thegene. To the best of our knowledge, this is the first case described inliterature involving only exon 6. The findings in our patients support thenotion that position of the alteration in TCF4 is relevant to the phenotype.Reporting our case we want to contribute to the phenotype-genotype correlationin patients with intragenomic deletion of TCF4 gene.