Clinical and Neuroimaging Findings in Children with Pathogenic Variants in PCDH12 Gene: Report of Four Cases from South India

INTRODUCTION: Protocadherins (PCDHs) are a family of cell-surface proteins that belong to the cadherin superfamily. PCDH12 is widely expressed in human tissues, including the lung, placenta, spleen, and brain. Loss-of-function variants in the protocadherin12 (PCDH12) gene have been implicated in an autosomal recessive disorder characterized by microcephaly, seizures, spasticity, and brain calcifications. Here, we describe the clinical, neuroimaging, and genotypic findings in four unrelated children with pathogenic or likely pathogenic biallelic variants in the PCDH12 gene. CASE SUMMARY: Our patients had global developmental delay, dysmorphic features, microcephaly, axial hypotonia, spasticity, dystonia, and ataxia. Three of our patients exhibited early-onset seizures from infancy with variable semiology. Neuroimaging in our patients revealed diencephalic-mesencephalic junction dysplasia (DMJD), enlargement of the lateral ventricles, hypoplasia of the corpus callosum, butterfly sign in the midbrain, and dysmorphic basal ganglia. Brain calcification was not observed in our patients. The constellation of clinical and imaging findings in PCDH12-related DMJD may be attributable to alterations in the formation and maintenance of neural circuits. Our patients 1 and 2 harbored novel frameshift variants in the PCDH12 gene, and patient 4 harbored novel nonsense variants in the PCDH12 gene, while patient 3 had previously reported nonsense variants resulting in a truncated protein that might have resulted in severe functional defects. CONCLUSION: This case series expands the phenotypic, neuroimaging, and genotypic spectrum in patients with biallelic variants in the PCDH12 gene.