Genetic Analysis of Pitt-Hopkins Syndrome Caused by a Novel Splicing Variant (c.1146+3A>T) in the TCF4 Gene

Pitt-Hopkins Syndrome (PTHS) is a rare genetic disorder primarily caused by TCF4 mutations and involves developmental, intellectual, and physical changes in children. Increased nuchal translucency (NT) has not been associated with TCF4 mutations or PTHS. Here we study the connection between increased NT and a c.1146+3A>T mutation in the TCF4 gene.

The genetic basis of increased NT in an early pregnancy fetus was investigated by family trio clinical exome sequencing (CES) using fetal amniotic fluid and parental peripheral blood samples. The candidate variant was validated by Sanger sequencing. The impact of the variant on transcription was assessed using a minigene assay.

Early ultrasound revealed an NT measurement of 3.5 mm in fetus B of a twin pregnancy. CES identified a de novo heterozygous c.1146+3A>T variant in intron 14 of TCF4, confirmed by Sanger sequencing. In vitro minigene experiments showed that the mutation disrupted TCF4 mRNA splicing, resulting in exon 14 skipping and a truncated transcript.

Our results identified c.1146+3A>T as a novel splicing variant of the TCF4. The TCF4 c.1146+3A>T mutation may underlie increased NT in early pregnancy, suggesting that increased NT could be an early intrauterine sign of PTHS.