Pontocerebellar Hypoplasia and Periventricular Leukomalacia Associated With p.Phe262Val Homozygous Variant in TTC1 Gene: A Report of 4 Cases

Abstract

Objective: Pontocerebellar hypoplasia (PCH) encompasses a heterogeneous group of neurodevelopmental disorders, currently comprising 28 subtypes listed in the Online Mendelian Inheritance in Man (OMIM) database (as of May 2025). No clinical phenotype has been associated with the TTC1 gene in OMIM. In this report, we present four female patients from two unrelated families exhibiting PCH with cerebral periventricular leukomalacia and additional clinical features potentially linked to TTC1. Case Presentations: All four affected individuals presented with global developmental delay. Physical examination revealed axial hypotonia, microcephaly and esotropia. Neuroimaging (brain MRI) consistently demonstrated PCH, reduced white matter volume and ventriculomegaly secondary to periventricular leukomalacia. Genomic DNA extracted from peripheral blood samples of the affected individuals, their unaffected parents and siblings was analyzed using trio-based whole-exome sequencing. Variant prioritization was performed via the RD-Connect Genome–Phenome Analysis Platform, which identified a homozygous missense variant in TTC1 (NM_003314.3: c.784 T > G, p.Phe262Val) in all affected individuals. The variant was present in the heterozygous state in all parents and unaffected siblings. This variant is classified as likely pathogenic in the ClinVar database. Result: Our findings in four patients confirm that this variant in the TTC1 gene may be associated with PCH and cerebral periventricular leukomalacia. To our knowledge, this is the first report implicating TTC1 in congenital brain malformations. We propose that TTC1 should be considered a candidate gene in the genetic evaluation of patients with PCH and related cerebral abnormalities. © 2025 Elsevier B.V., All rights reserved.