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Novel comprehensive diagnostic strategy in Pitt–Hopkins syndrome: Clinical score and further delineation of the TCF4 mutational spectrum
Author(s) -
Whalen Sandra,
Héron Delphine,
Gaillon Thierry,
Moldovan Oana,
Rossi Massimiliano,
Devillard Françoise,
Giuliano Fabienne,
Soares Gabriela,
MathieuDramard Michelle,
Afenjar Alexandra,
Charles Perrine,
Mignot Cyril,
Burglen Lydie,
Van Maldergem Lionel,
Piard Juliette,
Aftimos Salim,
Mancini Grazia,
Dias Patricia,
Philip Nicole,
Goldenberg Alice,
Le Merrer Martine,
Rio Marlène,
Josifova Dragana,
Van Hagen Johanna Maria,
Lacombe Didier,
Edery Patrick,
DupuisGirod Sophie,
Putoux Audrey,
Sanlaville Damien,
Fischer Richard,
Drévillon Loïc,
BriandSuleau Audrey,
Metay Corinne,
Goossens Michel,
Amiel Jeanne,
Jacquette Aurelia,
Giurgea Irina
Publication year - 2012
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21639
Subject(s) - missense mutation , haploinsufficiency , tcf4 , biology , genetics , hum , gene , point mutation , bioinformatics , mutation , transcription factor , phenotype , enhancer , art , performance art , art history
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.