Pontocerebellar Hypoplasia and Periventricular Leukomalacia Associated With p.Phe262Val Homozygous Variant in TTC1 Gene: A Report of 4 Cases
Funding: The study is supported by TUBITAK (The Scientific and Technological Research Council of Turkey) Project No. 216S771. Y.O. is supported by the Turkish Academy of Sciences' Young Investigator award, TUBA-GEBIP (2017). R.H. was supported by the European Research Council [309548], the Wellcome Investigator Award [109915/Z/15/Z]. the Medical Research Council (UK) [MR/N025431/1]; the Wellcome Trust Pathfinder Scheme [201064/Z/16/Z], the Newton Fund [UK/Turkey, MR/N027302/1], the Lily Foundation, the Stoneygate Trust, the Evelyn Trust and the Addenbrookes Charitable Trust (G100142). HL receives support from the Canadian Institutes of Health Research (CIHR) for Foundation Grant FDN-167281 (Precision Health for Neuromuscular Diseases), Transnational Team Grant ERT-174211 (ProDGNE) and Network Grant OR2-189333 (NMD4C), from the Canada Foundation for Innovation (CFI-JELF 38412), the Canada Research Chairs program Canada Research Chair in Neuromuscular Genomics and Health, (950-232279), the European Commission (Grant # 101080249) and the Canada Research Coordinating Committee New Frontiers in Research Fund (NFRFG-2022-00033) for SIMPATHIC, and from the Government of Canada Canada First Research Excellence Fund (CFREF) for the Brain-Heart Interconnectome (CFREF-2022-00007).
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.
Conflicts of Interest
The authors declare no conflicts of interest.
Open Research
Data Availability Statement
The data of Cases 1, 2 and 3 that support the findings of this study are openly available in (Hiz Kurul et al. 2022) at https://doi.org/10.1093/brain/awab395. Case 4's data generated or analyzed during this study are included in this. Further inquiries can be directed to the corresponding author.
