The Phenotypic Spectrum of PCDH12-Associated Disorders: Five New Cases and Review of the Literature

Background: PCDH12 is a member of the non-clustered protocadherin family of calcium-dependent cell adhesion proteins, which are involved in the regulation of brain development and endothelial adhesion. To date, only 15 families have been reported with PCDH12-associated disease.

Methods: In this study, we reviewed the literature and report the clinical course, imaging data, and the genetic findings of three pediatric and two adult patients with homozygous truncating mutations in PCDH12. Possible systemic activation of type I interferon was assessed by expression analysis of interferon-stimulated genes in peripheral blood lymphocytes of the pediatric cases.

Results: We present a comprehensive overview on the clinical spectrum associated with PCDH12 deficiency highlighting the main features such as developmental delay, movement disorder, epilepsy, microcephaly, visual impairment, midbrain malformations, and intracranial calcifications.

In addition, we report novel clinical features such as late-onset epilepsy, episodes of transient developmental regression, and dysplasia of the medulla oblongata associated with novel truncating PCDH12 mutations in five cases, three children, and two adults.

Interestingly, our data suggests a clinical overlap with interferonopathies. The interferon score was elevated in two of the pediatric patients.

Conclusion: This case series expands the genetic and phenotypic spectrum of PCDH12-associated diseases and highlights the broad clinical variability. Interferon activation should be considered as part of the pathomechanism in PCDH12-related disease.

^*These are the shared first authors.

Publication History

Article published online:
28 October 2021