Novel compound heterozygous variant of TOE1 results in a mild type of pontocerebellar hypoplasia type 7: an expansion of the clinical phenotype.

The target of EGR1 protein 1 (TOE1) is a 3-exonuclease belonging to the Asp-Glu-Asp-Asp deadenylase family that plays a vital role in the maturation of a variety of small nuclear RNAs (snRNAs). Bi-allelic variants in TOE1 have been reported to cause a rare and severe neurodegenerative syndrome, pontocerebellar hypoplasia type 7 (PCH7) (OMIM # 614,969), which is characterized by progressive neurodegeneration, developmental delay, and ambiguous genitalia. Here, we describe the case of a 5-year-6-month-old female Chinese patient who presented with cerebral dysplasia, moderate intellectual disability, developmental delay, and dystonia. Trio whole-exome sequencing revealed two previously unreported heterozygous variants of TOE1 in the patient, including a maternal inherited splicing variant c.237-2A > G and a de novo missense variant c.551G > T, p.Arg184Leu. TA clone sequencing showed trans status of the two variants, indicating the missense variant occurred on the paternal strand in the patient. Clinical features of the patient were mostly concordant with previous reports but brain deformities (enlarged lateral ventricle and deepened cerebellum sulcus without microcephaly and reduced cerebellar volume) were less severe than in typical PCH7 patients. Moreover, the patient had no gonadal malformation, which is common and variable in patients with PCH7. In summary, we report the case of a Chinese patient with atypical PCH7 caused by a novel TOE1 compound variant. Our work suggests that variations in the TOE1 gene can lead to highly variable clinical phenotypes.