Functionalisation of de-novo synonymous variant in TCF4 associated with Pitt-Hopkins syndrome: a case report and review of literature

Pitt-Hopkins syndrome (PTHS) (MIM #610954) is a rare genetic disorder caused by haploinsufficiency of the transcription factor 4 (TCF4) gene. While its overall prevalence is unknown, the frequency of PTHS is estimated around 1 in 11 000 (Sweetser et al., 1993). The clinical features of PTHS include developmental delay, speech deficits, distinctive facial features, recurrent seizures and breathing problems such as episodic hyperventilation and breath holding (Goodspeed et al., 2018). While inheritance of PTHS is autosomal dominant, most cases of PTHS are not inherited and occur sporadically due to a de-novo variant involving the TCF4 gene. Whole-exome sequencing (WES)/whole-genome sequencing has significantly improved the diagnostic yield and shortened the diagnostic odyssey in patients with rare Mendelian disorders (Matthijs et al., 2016; Souche et al., 2022; Wojcik et al., 2024). However, for over 40% of cases undergoing genetic testing variants are identified whose significance is not clear (Chen et al., 2023). These variants, known as variants of uncertain significance (VUS), lead to uncertainty in genetic diagnoses. Here, we report a case of a 7-year-old boy with clinical features of PTHS, and a synonymous variant in TCF4 gene, where subsequent functionalisation showed potential disruption to splicing giving rise to altered protein, hence supporting pathogenicity of the variant.