Haploinsufficiency of TCF4 Causes Syndromal Mental Retardation with Intermittent Hyperventilation (Pitt-Hopkins Syndrome)

Abstract

Pitt-Hopkins syndrome is a rarely reported syndrome of so-far-unknown etiology characterized by mental retardation, wide mouth, and intermittent hyperventilation. By molecular karyotyping with GeneChip Human Mapping 100K SNP arrays, we detected a 1.2-Mb deletion on 18q21.2 in one patient. Sequencing of the TCF4 transcription factor gene, which is contained in the deletion region, in 30 patients with significant phenotypic overlap revealed heterozygous stop, splice, and missense mutations in five further patients with severe mental retardation and remarkable facial resemblance. Thus, we establish the Pitt-Hopkins syndrome as a distinct but probably heterogeneous entity caused by autosomal dominant de novo mutations in TCF4. Because of its phenotypic overlap, Pitt-Hopkins syndrome evolves as an important differential diagnosis to Angelman and Rett syndromes. Both null and missense mutations impaired the interaction of TCF4 with ASCL1 from the PHOX-RET pathway in transactivating an E box-containing reporter construct; therefore, hyperventilation and Hirschsprung disease in patients with Pitt-Hopkins syndrome might be explained by altered development of noradrenergic derivatives.

A gene dosage map of Chromosome 18: A map with clinical utility

“…Because this gene is known to be disease causing in the hemizygous state, it is classified as being haploinsufficient. 7 Indeed, the phenotype of individual 18q-195C is consistent with PittHopkins syndrome.…”

Clinical and genetic aspects of Angelman syndrome

“…53 Motor apraxia, severe speech deficits, excessive laughter, a very happy disposition, hyperactivity, a short attention span, mouthing of objects, tantrums, and stereotyped movements have been reported in female sibs by Gitiaux et al 54 The characteristic features of Pitt-Hopkins syndrome are mental retardation, wide mouth and distinctive facial features, and intermittent hyperventilation followed by apnea. 55 It may have overlapping features with AS such as microcephaly, seizures, ataxic gait, and happy personality. Diurnal hyperventilation is a salient feature in some and occurs after 3 years of age.…”

Impact of TCF4 on the genetics of schizophrenia

“…In this study, an interaction of TCF4 and MATH1, a proneural protein, on different neural progenitor populations was investigated and disrupted pontine nucleus development was found in TCF4 knock out mice. Second, several studies showed that TCF4 haploinsufficiency contributes to severe neurodevelopmental disorders such as the Pitt-Hopkins syndrome [1,4,9,33,40]. This autosomal dominant encephalopathy is characterized by severe mental retardation, microcephaly, disrupted motor development, and hyperventilation, as described above [25].…”

“…In the present review, we want to focus on the gene named transcription factor 4 (TCF4). In 2007, disruption of the TCF4 gene was shown to cause Pitt-Hopkins syndrome [1,4,40]. Pitt-Hopkins syndrome was described in 1978 as a syndrome of mental retardation, microcephaly, facial dysmorphisms, and intermittent hyperventilation [25].…”