TCF4 deletions in Pitt-Hopkins Syndrome.
Pitt-Hopkins syndrome (PHS) is a probably underdiagnosed, syndromic mental retardation disorder, marked by hyperventilation episodes and characteristic dysmorphism (large beaked nose, wide mouth, fleshy lips, and clubbed fingertips). PHS was shown to be caused by de novo heterozygous mutations of the TCF4 gene, located in 18q21. We selected for this study 30 unrelated patients whose phenotype overlapped PHS but which had been initially addressed for Angelman, Mowat-Wilson, or Rett syndromes. In 10 patients we identified nine novel mutations (four large cryptic deletions, including one in mosaic, and five small deletions), and a recurrent one. So far, a total of 20 different TCF4 gene mutations have been reported, most of which either consist in deletion of significant portions of the TCF4 coding sequence, or generate premature stop codons. No obvious departure was observed between the patients harboring point mutations and large deletions at the 18q21 locus, further supporting TCF4 haploinsufficiency as the molecular mechanism underling PHS. In this report, we also further specify the phenotypic spectrum of PHS, enlarged to behavior, with aim to increase the rate and specificity of PHS diagnosis.
Giurgea
Irina
I
INSERM U841, IMRB, Département de Génétique, Equipe 11, Créteil, F-94000, France. irina.giurgea@inserm.fr
Missirian
Chantal
C
Cacciagli
Pierre
P
Whalen
Sandra
S
Fredriksen
Tessa
T
Gaillon
Thierry
T
Rankin
Julia
J
Mathieu-Dramard
Michele
M
Morin
Gilles
G
Martin-Coignard
Dominique
D
Dubourg
Christèle
C
Chabrol
Brigitte
B
Arfi
Jacqueline
J
Giuliano
Fabienne
F
Claude Lambert
Jean
J
Philip
Nicole
N
Sarda
Pierre
P
Villard
Laurent
L
Goossens
Michel
M
Moncla
Anne
A
D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002887:Chromosomes, Human, Pair 18; D018388:Codon, Terminator; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000235:genetics; D005260:Female; D006801:Humans; D006985:Hyperventilation / Q000235:genetics; D008607:Intellectual Disability / Q000235:genetics*; D007621:Karyotyping; D008297:Male; D009154:Mutation; D010641:Phenotype; D017384:Sequence Deletion; D013577:Syndrome; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein
D018388:Codon, Terminator; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein