Genetic and prenatal diagnosis of a Chinese pedigree with pathogenic TOE1 variants causing pontocerebellar hypoplasia type 7

Abstract

Objective: Biallelic pathogenic variants in TOE1 cause pontocerebellar hypoplasia type 7 (PCH7), a rare neurological condition characterized by psychomotor retardation, spastic paraplegia, seizures, gonadal abnormalities and brain anomalies. Currently, only 14 postnatally diagnosed PCH7 patients have been described. However, the prenatal clinical profile of PCH7 has not yet been reported.

Method: Whole-exome sequencing (WES) was performed to screen for causal variants.

Results: We report the pedigree of a Chinese woman with two eventful pregnancies with fetuses that showed brain anomalies, including microcephaly, cerebral anomalies, enlarged ventricles, corpus callosum thinning, abnormal lateral fissure, underdeveloped insula and pons and brainstem hypoplasia. Interestingly, corpus callosum thinning was observed in fetus 1 but not in fetus 2. An abnormal lateral fissure and an underdeveloped insula were shown in fetus 2 but not fetus 1. Biallelic variants c.716T > C (p.Phe239Ser) and c.955C > T (p.His319Tyr) in TOE1 were identified in both fetuses.

Conclusion: We first describe the prenatal features of a Chinese pedigree with PCH7 caused by biallelic pathogenic variants in TOE1, with phenotypic variability observed even within the same family. Novel phenotypes, an abnormal lateral fissure and an underdeveloped insula were observed in the fetus in our study. These findings will enrich our knowledge of the clinical characteristics, management and genetic counseling of PCH7.

Keywords:

• TOE1
• pontocerebellar hypoplasia type 7
• prenatal diagnosis
• genetic counseling

Acknowledgments

We would like to express our sincere gratitude to the families for their cooperation.

Ethics approval

This study was approved by the Ethics Committee of Dongguan Maternal and Child Health Care Hospital.

Authors’ contributions

HMG and ZXD drafted the first versions of the manuscript. HMY was responsible for the design of the project, data analysis, and revising the manuscript. QHX, ZW and XMZ collected clinical information on the fetuses in detail. XCH coordinated the clinical evaluation. QMW and YS performed the experiments and data entry. All authors read and approved the final manuscript.

Patient consent

Written informed consent was obtained from the legal guardians for the publication of any potentially identifiable images or data included in this article.

Consent for publication

Consent to publish has been obtained from the parents of the pedigree.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This study was supported by the Dongguan Social Development Project (No. 20211800904742 to Yan Sun). The funding body participated in the design of the project and interpretation of whole exome sequencing.