Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: Clinical score and further delineation of the TCF4 mutational spectrum
2 CRICM - Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière
3 CHU Henri Mondor [Créteil]
4 Hospital de Santa Maria [Lisboa]
5 Groupement Hospitalier Est, Hospices Civils de Lyon
6 CHUGA - CHU de Grenoble-Alpes - Centre Hospitalier Universitaire CHU Grenoble
7 Hôpital l'Archet
8 INSA - Porto (Portugal)
9 CHU Amiens-Picardie
10 CHU Trousseau [APHP]
11 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
12 Auckland City Hospital
13 Erasmus MC - Erasmus University Medical Center [Rotterdam]
14 TIMONE - Hôpital de la Timone [CHU - APHM]
15 CHU Rouen
16 Hôpital Necker - Enfants Malades [AP-HP]
17 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement
18 Guy's and St Thomas' Hospital [London]
19 VU University Medical Center [Amsterdam]
20 CHU Bordeaux - Centre Hospitalier Universitaire de Bordeaux
21 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
22 JCU - James Cook University
23 IMRB - Institut Mondor de Recherche Biomédicale
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Résumé
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.