NGS techniques to explore unusual TCF4 mutations and genetic heterogeneity in patients with Pitt-Hopkins syndrome phenotype

Pitt-Hopkins syndrome is a rare, but emerging genetic condition falling within syndromic forms of severe intellectual disability. The major causative gene, TCF4, was indentified in 2007. Mutations in TCF4 usually occur de novo in patients, making the familial recurrence risk in subsequent pregnancies negligible. However mutations in different genes can cause a similar clinical presentation. Some of these gene are already known, and they are responsible for autosomal-recessive forms of this condition, making the recurrence risk in subsequent pregnancies as high as 25%. Several patients have no detectable mutations in the already known genes, preventing the genetic diagnosis and genetic counselling in families. The currently available techniques for deep genomic investigation, in particular sequencing of the whole exoma, can change this scenario. When applied in connection with fine clinical evaluation of patients, these techniques can allow the discovery of new causative genes.This first step will lead to a much better elucidation of disease mechanisms that in turn should facilitate development of improved diagnostics, prevention strategies and targeted therapeutics. Although severe intellectual disability is expected not to reverse by drugs, other key features, such as epilepsy, could be, likely preventing the progression of the epileptic encephalopathy.