PCDH19 – Developmental and Epileptic Encephalopathy 9

Protocadherin-19, encoded by the PCDH19 gene, is a calcium-dependent cell adhesion molecule expressed in the developing brain. Heterozygous pathogenic variants in PCDH19 cause Developmental and Epileptic Encephalopathy 9, an X-linked condition characterized by early-onset clustering seizures (HP:0001250), variable intellectual disability, and neuropsychiatric features. Unlike classic X-linked disorders, DEE9 affects heterozygous females and mosaic males, whereas hemizygous males are typically spared (PMID:38083988). This unusual cellular mosaicism leads to disrupted cell-cell interactions and network hyperexcitability.

The genetic architecture of DEE9 includes point mutations and copy-number variants. To date, four unrelated probands have been reported: a prenatal case with a 10.05-Mb microdeletion spanning PCDH19 (PMID:38083988); a de novo triplication of Xq21.3-q22.1 including PCDH19 (PMID:39457436); and two female siblings harboring a heterozygous frameshift, c.1091delC (p.Pro364ArgfsTer4), segregating via parental germline mosaicism (PMID:39553263). Two additional affected relatives (the siblings) demonstrate segregation of the c.1091delC variant (PMID:39553263).

The variant spectrum comprises loss-of-function alleles, including microdeletions, frameshifts (e.g., c.1091delC (p.Pro364ArgfsTer4)), and missense changes, as well as the novel dose-gain mechanism via gene triplication. No recurrent founder alleles have been described. Phenotypic variability extends from severe epileptic encephalopathy to autism (HP:0000717) and atypical behavior (HP:0000708).

Functional studies support a loss-of-function mechanism and cellular interference model. Crystallographic analysis revealed that missense mutations at the adhesive interface (e.g., p.Thr146Arg) abolish homophilic adhesion in vitro (PMID:27787195). HiPSC-derived mosaic neurons carrying frameshift mutations (e.g., c.2133del (p.Thr712ProfsTer8)) exhibit accelerated maturation and hyperexcitability, recapitulating DEE9 cellular phenotypes (PMID:37186408). Consistent with this, Pcdh19 mosaic mice display synaptic defects, reduced firing rates, and limbic hyperconnectivity (PMID:36997609).

No studies have refuted the PCDH19–DEE9 association. The convergence of genetic, segregation, and functional data yields a robust link. Both haploinsufficiency and aberrant dose gain disrupt network wiring, underscoring the sensitivity of cortical circuits to PCDH19 expression levels.

Clinically, identifying PCDH19 variants via sequencing or CNV analysis enables prenatal diagnosis and targeted genetic counseling. Early molecular diagnosis informs prognosis, guides therapeutic strategies, and supports family planning. Key take-home: PCDH19 pathogenic dosage imbalance and loss-of-function variants robustly underlie DEE9, and genetic testing is essential for accurate diagnosis and management.

References

• Molecular genetics & genomic medicine • 2024 • Prenatal diagnosis of developmental and epileptic encephalopathy 9 with a 10.05-Mb microdeletion at Xq21.31q22.1 inherited from mother: A case report and literature review. PMID:38083988
• Genes • 2024 • Triplication of the PCDH19 Gene as a Novel Disease Mechanism Leading to Epileptic Encephalopathy Resembling Loss-of-Function Pathogenic Variants. PMID:39457436
• Basic and clinical neuroscience • 2024 • A Case Report of Parental Germline Mosaicism in the PCDH19 Gene of Two Iranian Siblings. PMID:39553263
• eLife • 2016 • Structural determinants of adhesion by Protocadherin-19 and implications for its role in epilepsy. PMID:27787195
• Epileptic disorders : international epilepsy journal with videotape • 2023 • Modeling PCDH19 clustering epilepsy by Neurogenin 2 induction of patient-derived induced pluripotent stem cells. PMID:37186408
• Molecular psychiatry • 2024 • Neuronal network activity and connectivity are impaired in a conditional knockout mouse model with PCDH19 mosaic expression. PMID:36997609

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