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Intellectual disability

Gene: PCDH12

Green List (high evidence)
PCDH12 (protocadherin 12)
EnsemblGeneIds (GRCh38): ENSG00000113555
EnsemblGeneIds (GRCh37): ENSG00000113555
OMIM: 605622, Gene2Phenotype
PCDH12 is in 14 panels

4 reviews

Catherine Snow (Genomics England)

Comment on list classification: Following review by Konstantinos Varvagiannis on PCDH12, highlighted that here is now a sufficient number of published variants from unrelated families to classify PCDH12 as Green with ID reported in all.
Created: 24 Oct 2019, 3:10 p.m. | Last Modified: 24 Oct 2019, 3:10 p.m.
Panel Version: 2.1081
Created: 24 Oct 2019, 3:10 p.m.
Last Modified: 24 Oct 2019, 3:10 p.m.
Panel version: 2.1081

Konstantinos Varvagiannis (Other)

Since the initial publications previously considered, there are several additional individuals with biallelic PCDH12 LoF variants reported in the literature. ID was a feature in almost all. Given the # of relevant articles, the gene was briefly reviewed.

[1] - PMID: 27164683 (Aran et al., 2016) - 10 patients from 4 consanguineous Palestinian families. All subjects of relevant age for whom clinical details were provided (belonging to 3 families), had profound DD. All affecteds were homozygous for a stopgain variant (NM_016580.3:c.2515C>T / p.Arg839Ter) - supported by broader segregation studies.
[2] - PMID: 28804758 (Nicolas et al., 2017) - Reports on brain images of a child that previously reported (not further considered). Screening a cohort of patients with brain calcifications, yielded 4 individuals with heterozygous ultrarare missense variants, present also in ExAC. Due to the uncertain effect of heterozygosity and the variant frequencies, the authors concluded that presence of the missense SNVs is not consistent with a causative effect.
[3] - PMID: 29556033 (Suzuki-Muromoto et al. 2018) - A japanese patient compound heterozygous for 2 truncating variants is described. Severe ID was part of the phenotype. The following variants were identified: c.448_449del:p.(Leu150Alafs*11) in trans with c.522_525del:p.(Ser175Profs*22) (confirmed by Sanger sequencing of the proband his parents).
[4] - PMID: 30178464 (Guemez-Gamboa et al., 2018) - 14 individuals from 8 families. ID was a feature in all. All were homozygous for stopgain/frameshift variants (5 different).
[5] - PMID: 30459466 (Vineeth et al., 2019) - Two sibs homozygous for a stopgain variant (NM_016580.3:c.2008G>T / p.Glu670*) presenting with cerebellar ataxia, dystonia, retinopathy, and dysmorphism. One had seizures. DD and ID were *NOT* observed. The same applied for calcifications upon brain imaging.

Arguments to support involvement of PCDH12 included some rather consistent features (ID,seizures,calcifications, etc) despite +variability, broad segregation studies, reduced transcript expression (by 84% in blood in ref1), reduced/absent protein levels in transfected 293T cells (ref4 - 3 variants tested), studies using patient derived iPSCs -> Neural precursor cells / endothelial cells (reduced expression by RT-PCR in the 2 latter, significant reduction in neurite length)(ref4), ubiquitous expression (also in fetal/adult fore-/hind-brain) evaluated by RT-PCR (ref4) as well as in available datasets (http://biogps.org/#goto=genereport&id=51294) (expression is much higher in other tissues, though).

In mouse, Pcdh12 is mainly/almost exclusively expressed in the placenta (with 500x lower expression in brain - commented in Ref1). Knockout mice are viable and fertile and present morphological alterations in the placenta. Placental and embryo growth were lower. The authors focused their study on the placenta where transcriptional changes were significantly altered for >2200 genes. Other phenotypes were not studied/commented on (PMID: 18477666).
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In OMIM the phenotype associated with biallelic PCDH2 mutations is Microcephaly, seizures, spasticity, and brain calcification (MIM 251280 - AR). There is no associated phenotype in G2P. PCDH2 is listed among the current primary ID genes. Some diagnostic laboratories (eg. GeneDx) include this gene in their ID panels.
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As a result, this gene could be considered for upgrade to green (rather than amber).
Created: 6 Oct 2019, 7:28 p.m. | Last Modified: 6 Oct 2019, 7:28 p.m.
Panel Version: 2.1062

Phenotypes
Microcephaly, seizures, spasticity, and brain calcification, 251280

Publications

Variants in this GENE are reported as part of current diagnostic practice

Created: 6 Oct 2019, 7:28 p.m.
Last Modified: 6 Oct 2019, 7:28 p.m.
Panel version: 2.1062

Ellen McDonagh (Genomics England Curator)

Red List (low evidence)

This gene was added and reviewed by an external reviewer as red to the Epilepsy Plus gene panel on 10th May 2017. One study reporting multiple consanguineous families with the same founder mutation, for a recessive syndrome characterized by prenatal hyperechogenic brain foci, congenital microcephaly, hypothalamic midbrain dysplasia, epilepsy, and profound global developmental disability.
Created: 18 Dec 2017, 12:30 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
intellectual disability; microcephaly; epilepsy; perithalamic hyperechogenicity; periventricular hyperechogenicity; midbrain abnormalities; hypothalamic abnormalities

Publications

Created: 18 Dec 2017, 12:26 p.m.

Panel version: 1.507

Cristina Dias (The Francis Crick Institute)

Red List (low evidence)

4 consanguineous families with the same mutation (c.2515C.T, p.R839X) described by Aran et al (2016) Neurology 86(21):2016-2024.
Created: 10 May 2017, 9:15 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
intellectual disability; microcephaly; epilepsy; perithalamic hyperechogenicity; periventricular hyperechogenicity; midbrain abnormalities; hypothalamic abnormalities

Publications

Created: 10 May 2017, 9:15 a.m.

Panel version: Imported from Epilepsy Plus panel version 0.7

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Expert Review
Phenotypes
  • intellectual disability
  • microcephaly
  • epilepsy
  • perithalamic hyperechogenicity
  • periventricular hyperechogenicity
  • midbrain abnormalities
  • hypothalamic abnormalities
  • Microcephaly, seizures, spasticity, and brain calcification, 251280
Tags
founder-effect
OMIM
605622
Clinvar variants
Variants in PCDH12
Penetrance
None
Publications
Panels with this gene

History Filter Activity

24 Oct 2019, Gel status: 3

Set Phenotypes

Catherine Snow (Genomics England)

Phenotypes for gene: PCDH12 were changed from intellectual disability; microcephaly; epilepsy; perithalamic hyperechogenicity; periventricular hyperechogenicity; midbrain abnormalities; hypothalamic abnormalities to intellectual disability; microcephaly; epilepsy; perithalamic hyperechogenicity; periventricular hyperechogenicity; midbrain abnormalities; hypothalamic abnormalities; Microcephaly, seizures, spasticity, and brain calcification, 251280

24 Oct 2019, Gel status: 3

Entity classified by Genomics England curator

Catherine Snow (Genomics England)

Gene: pcdh12 has been classified as Green List (High Evidence).

24 Oct 2019, Gel status: 1

Set publications

Catherine Snow (Genomics England)

Publications for gene: PCDH12 were set to 27164683

12 Mar 2018, Gel status: 1

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

18 Dec 2017, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

PCDH12 was added to Intellectual disability panel. Sources: Expert Review

18 Dec 2017, Gel status: 1

Created

Ellen McDonagh (Genomics England Curator)

PCDH12 was created by Ellen McDonagh