Background: Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder that results from variants of TCF4 gene. PTHS follows an autosomal dominant inheritance pattern and the underlying pathological mechanisms of this disease are still unclear.
Methods: Whole-genome sequencing (WGS) was conducted to screen for potential pathogenic variant in a boy highly suspected of having a genetic disorder. PCR and Sanger sequencing were used to verify the effects of the variant. Serum TCF4 levels were measured by ELISA.
Results: We present a 4-year and 3-month-old Chinese boy clinically and molecularly diagnosed with PTHS. The proband experienced global development delay, and the preliminary clinical diagnosis was cerebral palsy. WGS identified a de novo heterozygous variant: c.*1A > G in the 3'UTR of the TCF4 gene as a potential cause of his condition. The variant was verified to cause aberrant mRNA splicing by PCR and the aberrant splicing was confirmed by Sanger sequencing.
Conclusion: The study identified and demonstrated the pathogenicity of a novel 3'UTR site TCF4 variant for the first time. This research enhances understanding of pathogenetic mechanisms of PTHS and aids genetic counseling and diagnosis.
Keywords: TCF4; Clinically diagnosed; Molecularly diagnosed; Pitt-Hopkins syndrome; Whole-genome sequencing.
© 2024. The Author(s).