PCDH12 – Diencephalic-Mesencephalic Junction Dysplasia Syndrome 1

PCDH12 biallelic loss-of-function variants cause diencephalic-mesencephalic junction dysplasia syndrome 1, an autosomal recessive neurodevelopmental disorder. This syndrome presents with global developmental delay, microcephaly, dystonia, ataxia, and characteristic diencephalic–mesencephalic junction malformation (PMID:33527719). In a 2021 series, a patient harboring a homozygous PCDH12 frameshift variant, c.669dup (p.Lys224fs), exhibited the cardinal DMJDS1 features together with exudative vitreoretinopathy (PMID:33527719). Ophthalmic alterations such as exudative retinopathy appear integral to the PCDH12-associated phenotype, highlighting a broader clinical spectrum than initially recognized.

PCDH12 encodes a non-clustered protocadherin involved in cell–cell adhesion at neuronal and vascular junctions. Biallelic LoF variants are predicted to disrupt cortical and midbrain development and vascular homeostasis in the retina, consistent with imaging and ophthalmic findings (PMID:34929393). No segregation analyses beyond singletons have been reported, and functional studies specific to DMJDS1 remain limited. Key Take-home: PCDH12 genetic testing should be considered in patients with DMJDS1 phenotypes, particularly when ophthalmic features are present.

References

• American Journal of Medical Genetics. Part A • 2021 • Ophthalmic phenotypes associated with biallelic loss-of-function PCDH12 variants. PMID:33527719
• European Journal of Medical Genetics • 2022 • PCDH12 variants are associated with basal ganglia anomalies and exudative vitreoretinopathy. PMID:34929393

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