PCDH19

Gene Facts

• HGNC Symbol: PCDH19 (HGNC:14270)
• HGNC Name: protocadherin 19
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: EFMR
• Alias symbols: KIAA1313, EIEE9
• %HI: 6.65
• pLI: 1
• LOEUF: 0.13
• Cytoband: Xq22.1
• Genomic Coordinates:

  GRCh37/hg19:	chrX:99546642-99665271
  GRCh38/hg38:	chrX:100291644-100410273

• MANE Select Transcript: NM_001184880.2 ENST00000373034.8
• Function: Calcium-dependent cell-adhesion protein. {ECO:0000250|UniProtKB:F8W3X3}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-6010
• ClinGen Curation ID: CCID:007626
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 02/14/2023

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• X-linked complex neurodevelopmental disorder

HI Evidence

• PUBMED: 18469813
  Dibbens et al (2008) report mutations in families with epilepsy and intellectual disabilities limited to females (EFMR) with no affected males. Sequencing of the entire PCDH19 ORF identified two nonsense mutations (shown to be subject to nonsense-mediated decay) and three frameshift changes, including a nonsense change 253C>T (Q85X) in family 2, nonsense change 2012C>G (S671X) in family 3, frameshift change 2030_2031 insT (L677fsX717) in family 4 and a frameshift change 357delC (I119fsX122) in family 5, and a frameshift change 1091_1092insC (P364fsX375) in the original EFMR-bearing family. X-inactivation was random for all affected females. All the five LOF variants were familial and inherited from healthy fathers.
• PUBMED: 19214208
  Depienne et al (2009) report a male patient with Dravet syndrome who is negative for SCN1A mutation with a de novo 890 deletion of PCDH19. FISH on fibroblasts showed 53% of cells were normal. This mosaicism would be consistent with the cellular inference model. Additionally, 5 other variants were identified in female probands; 3 nonsense (c.142G>T/p.Glu48X inherited, c.352G>T/p.Glu118X de novo, c.859G>T/p.Glu287X inherited) and 2 frameshift variants (c.506delC/p.Thr169SerfsX43 de novo and c.1036_1040dup/p.Asn347LysfsX23 inherited) were found in females with Dravet-like symptoms. All of the inherited variants identified in the females were inherited from fathers with reported typical development.
• PUBMED: 23712037
  Higurashi et al (2013) tested females with early-onset seizures and found 17 variants, including three de novo large deletions including several flanking genes though, four nonsense (p.L719* inherited, p.S350* inherited, p.R886* de novo, p.Y166* unknown), and three frameshift variants (p.D45GfsX43 inherited, p.Y366LfsX10 unknown, and p.K120RfsX3 unknown). One of the inherited nonsense variants was from a healthy father but was also present in two unaffected sisters (all three females had random X-inactivation).
• PUBMED: 21480887
  Nicola Specchio (2011) sequenced PCDH19 gene in patients with infantile or early childhood seizures onset, either focal or generalized, without an obvious etiology, and identified two de novo frameshift variants (p.Gln434GlufsX11 andp.Asp320GlyfsX22) in two female patients.
• PUBMED: 23334464
  J J T van Harssel (2013) screened 120 females suffering from Dravet-like epilepsy, 136 females with EFMR features and 20 males with ASD and reported six additional patients with loss of function PCDH19 variants, including three nonsense (p.Arg886X, p.Glu240X, p.Ser139X) and three frameshift variants (p.Gly622fs, p.Pro364fs, p.Tyr366fs). All six LOF variants were de novo.
• PUBMED: 36408521
  Yi Chen (2022) analyzed clinical data and peripheral blood samples of 11 male mosaic patients with PCDH19-related epilepsy (PCDH19-RE) and explore the correlation between genotype, variant allele frequency, and phenotypic severity. Among those 11 patients, 10 variants were identified, including two frameshift variants (p.I115Kfs*110 and p.D54Gfs*35) and two nonsense variants (p.Y280* and p.Y154*), one of the frameshift variants is a novel variant (p.I115Kfs*110) that has not been reported before. As those variants were identified in male mosaic patients, all the four LOF variants were assuming de novo.

• HI Evidence Comments: In addition to the papers listed above, variants in PCDH19 are reported in the following papers: PMIDs 22949144, 22848613, 22633638, 22091964, 21053371, 20830798, 20713952, and 19752159. X-inactivation patterns may vary clinical outcome. In a 2020 review article, Samanta describes the disorder as "primarily manifest[ing] in heterozygote females due to random X chromosome inactivation leading to somatic mosaicism and abnormal cellular interference between cells with and without delta-protocadherin" (PMID: 32057594). However, as described above, mosaic affected males have also been reported. The Epilepsy Gene Curation Expert Panel has decided to curate this gene for X-linked complex neurodevelopmental disorder (Mondo:0100038) because of the presence of ID/DD and epilepsy.

NOTE

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity

NOTE

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.