TOE1 – Pontocerebellar Hypoplasia Type 7

The association between TOE1 and pontocerebellar hypoplasia type 7 is supported by multiple independent case reports and family studies that collectively identify biallelic pathogenic variants in TOE1 leading to a neurodegenerative phenotype. Several studies document compound heterozygous variants in TOE1, demonstrating autosomal recessive inheritance, segregation in affected families, and variability in clinical presentation that includes intellectual disability, developmental delay, and brain malformations (PMID:34716526, PMID:37945020).

In these reports, clinical features frequently include global developmental delay, dystonia, and structural brain anomalies such as lateral ventricle dilatation and microcephaly, with additional findings such as micropenis and cryptorchidism in some patients. The consistency of these phenotypes across unrelated probands underscores the genetic association with pontocerebellar hypoplasia type 7 (PMID:37635087).

Genetic evidence is bolstered by the detection of diverse variant classes including missense and splicing events. For instance, one notable variant, c.911C>T (p.Ser304Leu), was identified among the reported cases. These findings are complemented by segregation analyses in several families, confirming the autosomal recessive mode of inheritance and reinforcing the role of TOE1 in disease causality (PMID:36738896).

Experimental studies further clarify the mechanism of pathogenicity by demonstrating that TOE1 functions as a 3' exonuclease involved in snRNA and telomerase RNA maturation. Knockout and rescue experiments have recapitulated key aspects of the patient phenotype, linking defective RNA processing to neurodegeneration (PMID:30371886, PMID:39502232).

Although some case reports highlight variable severity in brain malformations and extraneural features, the weight of genetic and functional evidence converges to a strong association between TOE1 variants and pontocerebellar hypoplasia type 7. The integration of data from multi‐patient studies, familial segregation, and rigorous mechanistic experiments emphasizes the clinical relevance of screening TOE1 in patients presenting with related neurodevelopmental disorders (PMID:28092684).

Key take‑home sentence: TOE1 is a strong, clinically actionable candidate for pontocerebellar hypoplasia type 7, with robust genetic and functional evidence supporting its role in disease pathogenesis.

References

• Neurogenetics • 2022 • Novel compound heterozygous variant of TOE1 results in a mild type of pontocerebellar hypoplasia type 7: an expansion of the clinical phenotype PMID:34716526
• Annals of Clinical and Laboratory Science • 2023 • Pontocerebellar Hypoplasia 7 with Novel Compound Heterozygous Variants of TOE1 in a Boy with Micropenis, Developmental Delay, and Ataxia: The First Korean Case Report PMID:37945020
• The Journal of Maternal-Fetal & Neonatal Medicine • 2023 • Genetic and prenatal diagnosis of a Chinese pedigree with pathogenic TOE1 variants causing pontocerebellar hypoplasia type 7 PMID:37635087
• Gene • 2023 • Novel compound heterozygous missense variants in TOE1 gene associated with pontocerebellar hypoplasia type 7 PMID:36738896
• Nature Genetics • 2017 • Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing PMID:28092684
• Nucleic Acids Research • 2019 • TOE1 acts as a 3' exonuclease for telomerase RNA and regulates telomere maintenance PMID:30371886
• Heliyon • 2024 • Toe1 promotes proliferation and differentiation of neural progenitor cells PMID:39502232

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