Communicated by Segoléne Ayme
Novel comprehensive diagnostic strategy in Pitt–Hopkins syndrome: Clinical score and further delineation of the TCF4 mutational spectrum†
Article first published online: 23 NOV 2011
© 2011 Wiley Periodicals, Inc.
Volume 33, Issue 1, pages 64–72, January 2012
How to Cite
Whalen, S., Héron, D., Gaillon, T., Moldovan, O., Rossi, M., Devillard, F., Giuliano, F., Soares, G., Mathieu-Dramard, M., Afenjar, A., Charles, P., Mignot, C., Burglen, L., Van Maldergem, L., Piard, J., Aftimos, S., Mancini, G., Dias, P., Philip, N., Goldenberg, A., Le Merrer, M., Rio, M., Josifova, D., Van Hagen, J. M., Lacombe, D., Edery, P., Dupuis-Girod, S., Putoux, A., Sanlaville, D., Fischer, R., Drévillon, L., Briand-Suleau, A., Metay, C., Goossens, M., Amiel, J., Jacquette, A. and Giurgea, I. (2012), Novel comprehensive diagnostic strategy in Pitt–Hopkins syndrome: Clinical score and further delineation of the TCF4 mutational spectrum. Hum. Mutat., 33: 64–72. doi: 10.1002/humu.21639
- Issue published online: 14 DEC 2011
- Article first published online: 23 NOV 2011
- Accepted manuscript online: 1 NOV 2011 04:00PM EST
- Manuscript Accepted: 15 OCT 2011
- Manuscript Received: 26 JUL 2011
- La Fondation Jérôme Lejeune
- Pitt–Hopkins syndrome;
- intellectual disability;
Pitt–Hopkins syndrome (PTHS), characterized by severe intellectual disability and typical facial gestalt, is part of the clinical spectrum of Rett-like syndromes. TCF4, encoding a basic helix-loop-helix (bHLH) transcription factor, was identified as the disease-causing gene with de novo molecular defects. While PTHS appears to be a recognizable clinical entity, it seems to remain underdiagnosed, especially when facial gestalt is less typical. With the aim to facilitate the diagnosis of PTHS and to increase its rate and specificity, we have investigated 33 novel patients and defined a Clinical Diagnosis Score. Analysis of 112 individuals (79 previously reported and 33 novel patients) allowed us to delineate the TCF4 mutational spectrum, with 40% point mutations, 30% small deletions/insertions, and 30% deletions. Most of these were private mutations and generated premature stop codons. Missense mutations were localized in the bHLH domain, which is a mutational hotspot. No obvious difference was observed between patients harboring truncating, missense mutations, or deletions, further supporting TCF4 haploinsufficiency as the molecular mechanism underlying PTHS. In this study, we have summarized the current knowledge of TCF4 molecular pathology, reported all the mutations in the TCF4 database (http://www.LOVD.nl/TCF4), and present a novel and comprehensive diagnostic strategy for PTHS. Hum Mutat 33:64–72, 2012. © 2011 Wiley Periodicals, Inc.