title: Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum.
abstract: 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.
authors: AP-HP, Groupe Hospitalier Pitié Salpêtrière, Unité Fonctionnelle de Génétique Clinique, Département de Génétique et Cytogénétique, Centre de Référence Maladies Rares, Déficiences Intellectuelles de Causes Rares, Paris, France.
authors: Sandra
authors: S
authors: Whalen
authors: Delphine
authors: D
authors: Héron
authors: Thierry
authors: T
authors: Gaillon
authors: Oana
authors: O
authors: Moldovan
authors: Massimiliano
authors: M
authors: Rossi
authors: Françoise
authors: F
authors: Devillard
authors: Fabienne
authors: F
authors: Giuliano
authors: Gabriela
authors: G
authors: Soares
authors: Michelle
authors: M
authors: Mathieu-Dramard
authors: Alexandra
authors: A
authors: Afenjar
authors: Perrine
authors: P
authors: Charles
authors: Cyril
authors: C
authors: Mignot
authors: Lydie
authors: L
authors: Burglen
authors: Lionel
authors: L
authors: Van Maldergem
authors: Juliette
authors: J
authors: Piard
authors: Salim
authors: S
authors: Aftimos
authors: Grazia
authors: G
authors: Mancini
authors: Patricia
authors: P
authors: Dias
authors: Nicole
authors: N
authors: Philip
authors: Alice
authors: A
authors: Goldenberg
authors: Martine
authors: M
authors: Le Merrer
authors: Marlène
authors: M
authors: Rio
authors: Dragana
authors: D
authors: Josifova
authors: Johanna Maria
authors: JM
authors: Van Hagen
authors: Didier
authors: D
authors: Lacombe
authors: Patrick
authors: P
authors: Edery
authors: Sophie
authors: S
authors: Dupuis-Girod
authors: Audrey
authors: A
authors: Putoux
authors: Damien
authors: D
authors: Sanlaville
authors: Richard
authors: R
authors: Fischer
authors: Loïc
authors: L
authors: Drévillon
authors: Audrey
authors: A
authors: Briand-Suleau
authors: Corinne
authors: C
authors: Metay
authors: Michel
authors: M
authors: Goossens
authors: Jeanne
authors: J
authors: Amiel
authors: Aurelia
authors: A
authors: Jacquette
authors: Irina
authors: I
authors: Giurgea
mesh_terms: D000293:Adolescent; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002887:Chromosomes, Human, Pair 18 / Q000737:chemistry / Q000235:genetics*; D030541:Databases, Genetic; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D005838:Genotype; D057895:Haploinsufficiency; D006239:Haplotypes; D006801:Humans; D006985:Hyperventilation / Q000175:diagnosis* / Q000235:genetics; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D057345:Sequence Inversion; D012720:Severity of Illness Index; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors