The TCF4 gene encodes a basic helix?loop?helix (bHLH) transcription
factor which belongs to the family of E-proteins. E-proteins form homoand
heterodimers with other members of the HLH family and bind to the
common DNA sequence called E-box. Haploinsufficiency of the TCF4
gene has been found to be associated with the Pitt?Hopkins syndrome
(PTHS). PTHS is characterized by severe mental retardation, a wide
mouth plus other distinctive facial features (fleshy lips, beaked nose, broad
nasal bridge) and breathing abnormalities. Because of some phenotypical
overlap with Angelman syndrome (AS), it has been suggested that PTHS
be considered in its differential diagnosis. To explore this possibility, we
screened 86 patients who were suspected of having AS. All the patients
were negative for UBE3A testing, and 53 were known to be negative for
methylation analysis. We identified two TCF4 mutations in this cohort.
The p.S384Tfsx7 mutation lacks the bHLH domain. The p.R582P
mutation lies within the bHLH domain in which seven other missense
mutations have been reported. Both mutations most likely affect the
critical function of the bHLH domain of the TCF4 protein. In summary,
we found two TCF4 mutations in 86 patients (2%) suspected to have AS.
Screening for mutations in this gene should be considered in patients who
present with findings of AS but who have been negative for methylation
and UBE3A testing.
Takano K, Lyons M, Moyes C, Jones J, Schwartz CE.
Clin Genet 2010.