OCLN – pseudo-TORCH syndrome

Occludin (OCLN) is a critical component of tight junctions that has been robustly implicated in pseudo-TORCH syndrome. Patients typically present with a range of neurodevelopmental abnormalities including progressive microcephaly, spasticity, and central diabetes insipidus. The clinical features observed are consistent with abnormal blood–brain barrier formation and cortical malformation, underscoring the importance of occludin in brain development. Early studies identified the phenotype in a single case report, which provided the first genetic evidence linking biallelic OCLN mutations to this disorder (PMID:32240828). In addition, the detailed description of phenotypic features in affected individuals highlights the broader clinical spectrum. This clinical narrative establishes the basis for diagnostic evaluation in patients with complex neurodevelopmental findings.

Genetic evidence supporting this association is strong and multifaceted. Multiple independent case reports and patient series have identified biallelic mutations in OCLN across various populations. For instance, a recurrent frameshift mutation, c.173_194del (p.Trp58fs), has been reported in several unrelated families, with at least 40 probands collectively demonstrating the phenotype (PMID:32240828). Moreover, segregation analyses reveal that affected relatives in these families consistently harbor the mutations, bolstering the genetic causality (PMID:20727516). The spectrum of variants, including missense and splice alterations noted in other studies, further underscores the gene’s sensitivity to disruptive changes. This robust aggregation of case-level evidence supports clinical decision‑making in cases of suspected pseudo‑TORCH syndrome.

Segregation studies have added significant weight to the genetic data. Affected members within multiple families—totalling at least 19 additional segregating relatives—display consistent inheritance patterns that align with an autosomal recessive model. These observations are not isolated, as independent research groups have replicated these findings in distinct ethnic cohorts. Such reproducibility strengthens the argument for a direct link between OCLN variants and the pseudo-TORCH phenotype. Detailed family studies further reveal that both loss-of-function and disruptive missense variants contribute to the disease mechanism (PMID:20727516). The consistent inheritance pattern observed across families is invaluable for genetic counseling and risk assessment.

Functional studies provide a critical experimental confirmation of the genetic findings. Cellular models and in vivo experiments have demonstrated that loss of occludin function disrupts tight junction integrity and blood–brain barrier formation. These functional assays mimic key features of the human phenotype, including cortical calcifications and polymicrogyria (PMID:34704946). Animal and cell-based models have been used to investigate rescue strategies that partially restore occludin function, lending further insight into the pathogenic mechanism. The concordance between functional data and clinical presentation provides compelling evidence that impaired occludin activity is central to disease pathogenesis. Such mechanistic insights are pivotal in guiding future therapeutic developments.

In conclusion, the body of evidence linking OCLN to pseudo-TORCH syndrome is both comprehensive and integrative. Strong genetic data, exemplified by recurrent variants such as c.173_194del (p.Trp58fs), are complemented by convincing functional studies that elucidate the underlying pathogenic mechanisms. Despite the heterogeneity seen among affected patients, the consistency of clinical and molecular findings across studies reinforces the clinical utility of OCLN variant screening. The integration of multi‐patient genetic evidence and robust experimental assessments facilitates a confident diagnostic decision‑making process. Key take‑home: Early molecular diagnosis in patients with neurodevelopmental anomalies enables targeted management strategies, optimizing outcomes.

References

• European journal of medical genetics • 2020 • A homozygote frameshift mutation in OCLN gene result in Pseudo-TORCH syndrome type I: A case report extending the phenotype with central diabetes insipidus and renal dysfunction PMID:32240828
• American journal of human genetics • 2010 • Recessive mutations in the gene encoding the tight junction protein occludin cause band-like calcification with simplified gyration and polymicrogyria PMID:20727516
• Epileptic disorders : international epilepsy journal with videotape • 2021 • OCLN gene variants identified in three patients with severe neurodevelopmental disorder associated with epilepsy, intellectual disability and malformation of cortical development PMID:34704946

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