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Title: Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome)
Authors: Zweier, Christiane ×
Peippo, Maarit M
Hoyer, Juliane
Sousa, Sergio
Bottani, Armand
Clayton-Smith, Jill
Reardon, William
Saraiva, Jorge
Cabral, Alexandra
Gohring, Ina
Devriendt, Koenraad
de Ravel, Thomy
Bijlsma, Emilia K
Hennekam, Raoul C M
Orrico, Alfredo
Cohen, Monika
Dreweke, Alexander
Reis, Andre
Nurnberg, Peter
Rauch, Anita #
Issue Date: May-2007
Series Title: American Journal of Human Genetics vol:80 issue:5 pages:994-1001
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.
URI: 
ISSN: 0002-9297
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Clinical Genetics
Clinical Genetics Section (-)
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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