Disruption of the TCF4 gene in a girl with mental retardation but without the classical Pitt-Hopkins syndrome.
We have characterized a de novo balanced translocation t(18;20)(q21.1;q11.2) in a female patient with mild to moderate mental retardation (MR) and minor facial anomalies. Breakpoint-mapping by fluorescence in situ hybridization indicated that on chromosome 18, the basic helix-loop-helix transcription factor TCF4 gene is disrupted by the breakpoint. TCF4 plays a role in cell fate determination and differentiation. Only recently, mutations in this gene have been shown to result in Pitt-Hopkins syndrome (PHS), defined by severe MR, epilepsy, mild growth retardation, microcephaly, daily bouts of hyperventilation starting in infancy, and distinctive facial features with deep-set eyes, broad nasal bridge, and wide mouth with widely spaced teeth. Breakpoint mapping on the derivative chromosome 20 indicated that here the rearrangement disrupted the chromodomain helicase DNA binding protein 6 (CHD6) gene. To date, there is no indication that CHD6 is involved in disease. Our study indicates that TCF4 gene mutations are not always associated with classical PHS but can give rise to a much milder clinical phenotype. Thus, the possibility exists that more patients with a less severe encephalopathy carry a mutation in this gene.
Kalscheuer
Vera M
VM
Max Planck Institute for Molecular Genetics, Berlin, Germany. kalscheu@molgen.mpg.de
Feenstra
Ilse
I
Van Ravenswaaij-Arts
Conny M A
CM
Smeets
Dominique F C M
DF
Menzel
Corinna
C
Ullmann
Reinhard
R
Musante
Luciana
L
Ropers
Hans-Hilger
HH
D000293:Adolescent; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002675:Child, Preschool; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D004268:DNA-Binding Proteins; D005145:Face / Q000002:abnormalities*; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008607:Intellectual Disability / Q000235:genetics*; D007621:Karyotyping; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013577:Syndrome; D051820:TCF Transcription Factors / Q000235:genetics*; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D014178:Translocation, Genetic
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D051820:TCF Transcription Factors; C532096:TCF4 protein, human; C544894:TCF7L2 protein, human; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors