The research on various haploinsufficiency mechanisms in Russian patients with Pitt-Hopkins syndrome

Pitt-Hopkins syndrome is a rare neurodevelopment disorder caused by haploinsufficiency of the transcription factor 4 (TCF4). The main clinical symptoms of Pitt-Hopkins syndrome are severe development delay, intellectual disability, characteristic facial phenotype, and breathing abnormalities, including episodic hyperventilation. Different pathogenic variants can lead to Pitt-Hopkins syndrome. The most common are large deletions at 18q21 encompassing the TCF4 gene and frame shifting / nonsense single nucleotide variants. However, variants in noncoding regions can also lead to Pitt-Hopkins syndrome by disrupting the normal pre-mRNA splicing machinery.

The study describes three patients with Pitt-Hopkins syndrome caused by a large deletion, a nonsense variant, and a novel variant located in intron 11 of TCF4 c.922+5G > A. A functional analysis was performed for the undescribed variant, which showed that this variant results in exon 11 skipping and formation of a premature stop codon. The study also compared phenotype of patients with different mechanisms of Pitt-Hopkins syndrome.

The researchers of the Functional Genomics laboratory, DNA diagnostics lab, Biobank SRC and physicians-geneticists of the FBSI RCMG Counselling Department conducted the research.

Peter Sparber, Alexandra Filatova, Inga Anisimova, Tatiana Markova, Viktoria Voinova, Alena Chuhrova, Vyacheslav Tabakov, Mikhail Skoblov. Various haploinsufficiency mechanisms in Pitt-Hopkins syndrome. European Journal of Medical Genetics. 2020 Oct 15:104088. doi: 10.1016/j.ejmg.2020.104088 (IF – 2,368, Q3)

https://www.sciencedirect.com/science/article/pii/S1769721220307989