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Diencephalic-mesencephalic junction dysplasia (Diencephalic-Mesencephalic Junction Dysplasia) is a rare autosomal recessive neurodevelopmental disorder characterized by progressive microcephaly, craniofacial dysmorphism, psychomotor disability, epilepsy, axial hypotonia, and variable appendicular spasticity with distinctive brainstem and basal ganglia malformations on MRI.
Initial evidence linking biallelic PCDH12 variants to this syndrome was reported in eight unrelated families harboring distinct loss-of-function alleles leading to absence of PCDH12 protein in neural and endothelial cells (PMID:30178464).
A subsequent report described two affected siblings from a ninth family with a homozygous nonsense variant, c.451C>T (p.Arg151Ter) (PMID:39119454), expanding the phenotypic spectrum to milder, cerebral palsy-like presentations. All DMJD-associated PCDH12 variants are protein-truncating (nonsense or frameshift), consistent with a loss-of-function mechanism under autosomal recessive inheritance.
Segregation analysis confirmed cosegregation of homozygous variants in affected sibs and carrier status in parents (2 additional affected relatives) (PMID:39119454).
Functional studies in patient-derived induced pluripotent stem cell–derived neural precursor and endothelial cells demonstrate complete loss of PCDH12 expression and significantly impaired neurite outgrowth, recapitulating key aspects of human brainstem malformation (PMID:30178464).
Heterozygous PCDH12 missense variants have been identified in primary familial brain calcification cohorts without truncating alleles or segregation data, arguing against a dominant mechanism in isolated calcification disorders (PMID:28804758).
Collectively, the genetic and experimental data provide strong evidence that autosomal recessive PCDH12 haploinsufficiency underlies diencephalic-mesencephalic junction dysplasia, supporting its inclusion in diagnostic gene panels and enabling accurate genetic counseling. Key take-home: biallelic PCDH12 truncating variants cause DMJD via loss-of-function, with robust functional concordance.
Gene–Disease AssociationStrong10 patients from 9 families with biallelic PCDH12 loss-of-function variants and segregation in 2 affected siblings; concordant functional data Genetic EvidenceStrong10 patients with autosomal recessive PCDH12 truncating variants across 9 families, reaching the genetic evidence cap Functional EvidenceModerateiPSC-derived neural precursor and endothelial cell models demonstrate loss of PCDH12 expression and impaired neurite outgrowth mirroring brainstem malformations |