Purpose: Pitt-Hopkins syndrome is characterized by severe mental retardation, characteristic dysmorphic features, and susceptibility to childhood-onset seizures and intermittent episodes of hyperventilation. This syndrome is caused by haploinsufficiency of TCF4, which encodes a basic helix-loop-helix transcription factor. Missense, nonsense, splicesite mutations, and gene deletions have been found in individuals with Pitt-Hopkins syndrome. Previous reports have suggested that the PittHopkins syndrome phenotype is independent of mutation or deletion type. Methods: We screened 13,186 individuals with microarray-based comparative genomic hybridization. We also conducted a review of the literature and statistical analysis of the phenotypic features for all individuals with confirmed mutations or deletions of TCF4. Results: We identified seven individuals with TCF4 deletions. All patients have features consistent with Pitt-Hopkins syndrome, although only three have breathing anomalies, and none has seizures. Our review of previously reported cases with TCF4 mutations and deletions showed that all patients with PittHopkins syndrome reported to date have severe psychomotor retardation, the onsets of seizures and hyperventilation episodes are limited to the first decade in most reported patients with Pitt-Hopkins syndrome, hyperventilation episodes are more common than seizures and are seen in the oldest patients, and individuals with missense TCF4 mutations are more likely to develop seizures. Conclusions: On the basis of an analysis of published cases, we propose a genotype-phenotype correlation of increased seizure activity with missense TCF4 mutations. itt-Hopkins syndrome (PTHS, OMIM 610954) was first described in 1978 1 in two individuals and is characterized by specific dysmorphic features (deep-set eyes, broad-beaked nose, wide mouth with bow-shaped upper lip, and widely spaced teeth), childhood-onset hyperventilation episodes, childhood-onset seizures, microcephaly, and severe psychomotor retardation with a happy disposition. It is an autosomal dominant condition caused by haploinsufficiency for TCF4 (transcription factor 4, OMIM 602272) on 18q21.2. [2][3][4] The etiology of PTHS was determined when two groups concurrently screened individuals with PTHS for chromosomal deletions using microarray technology, one with arraybased comparative genomic hybridization (aCGH) 5 and the other with single-nucleotide polymorphism-based molecular karyotyping. 3 Each group described a patient with a de novo deletion involving this gene. Further screening of individuals with PTHS or phenotypic overlap with PTHS found individuals with de novo missense and nonsense mutations in TCF4. 3,5 Subsequently, more individuals have been published with disruptions, deletions, and mutations in TCF4, most with typical PTHS features. 4,6 -10 TCF4 is a transcription factor that belongs to the class I basic helix-loop-helix (bHLH) protein family, also known as the "E-protein" family. These proteins form homo-and heterodimers with other heli...
