Palmoplantar keratoderma and erythrokeratodermas

Gene: GJA1

Green List (high evidence)

GJA1 (gap junction protein alpha 1)
EnsemblGeneIds (GRCh38): ENSG00000152661
EnsemblGeneIds (GRCh37): ENSG00000152661
OMIM: 121014, Gene2Phenotype
GJA1 is in 24 panels

2 reviews

Rebecca Foulger (Genomics England curator)

Comment on phenotypes: Removed phenotype 'Erythrokeratodermia variabilis et progressiva, 133200' because a June 2017 OMIM update now associates GJA1 with 'Erythrokeratodermia variabilis et progressiva 3, 617525'.
Created: 15 Aug 2017, 2:23 p.m.
Comment when marking as ready: Expert review Green. >3 cases from OMIM and literature supporting causation.
Created: 16 Mar 2017, 10:05 a.m.
Comment on mode of pathogenicity: PMID:16891658 (Gong et al., 2006) perform functional studies that suggest that frameshfit mutation fs260 (780-781del) dominantly negatively inhibits the wildtype protein.
Created: 16 Mar 2017, 10:03 a.m.
Comment on list classification: Updated rating from Amber to Green: 1 Green expert review. At least 3 disorders resulting from GJA1 mutations are relevant to this panel: PPK with congenital alopecia, 104100, Oculodentodigital dysplasia (ODDD, MIM:164200 and MIM:257850), and Erythrokeratodermia variabilis et progressiva (MIM:133200). Confirmed G2P gene for ODDD disorders, and >3 cases supporting causation for a PPK phenotype.
Created: 16 Mar 2017, 9:57 a.m.
Edel O'Toole provided publications (PMID:25388818, PMID:17256797) reporting oculodentodigital dysplasia (ODDD) patients with palmoplantar keratoderma (PPK). PPK is a minor symptom in patients with Oculodentodigital dysplasia (ODDD), and may be limited to specific mutations of GJA1.
Created: 16 Mar 2017, 9:55 a.m.
Comment on mode of inheritance: Reverted MOI back to 'both monoallelic and biallelic' based on reviewer recommendation. Oculodentodigital dysplasia (ODDD), which can present with PPK, is caused by mutations in GJA1, and can be dominantly (MIM:164200) or recessively (MIM:257850) inherited.
Created: 16 Mar 2017, 9:52 a.m.
Comment on list classification: Updated rating from Red to Amber ready for Expert review. >3 unrelated cases supporting the link between GJA1 and Palmoplantar keratoderma (OMIM:104100) or EKVP (OMIM:133200).
Created: 10 Jan 2017, 3:25 p.m.
Comment on mode of inheritance: Updated mode of inheritance from 'Both monoallelic and biallelic' to just monoallelic. Although OMIM report both biallelic and monoallelic causes of EKVP (OMIM:133200) for GJA1, GJB3 and GJB4, for GJA1 the literature reports heterozygous (monoallelic) mutations (PMID:25398053). Rare biallelic forms of EKVP (OMIM:133200) have so far just been reported for GJB3.
Created: 10 Jan 2017, 3:23 p.m.
Two GJA1 variants are recorded for 3 unrelated individuals with EKVP (OMIM:133200) by Boyden et al., 2015 (PMID:25398053). The same heterozygous missense mutation (E227D) is reported in a 32-month old boy (origin not specified) and a 6 year old girl (from Guatemala). Another heterozygous GJA1 mutation, A44V, was found in a third affected subject, a 30-year old woman (origin not specified). Erythrokeratodermia variabilis et progressiva (EKVP) is a rare, inherited skin disease that is characterized by transient figurate patches of erythema, localized or generalized scaling, and frequent palmoplantar keratoderma (PMID:25398053).
Created: 9 Jan 2017, 11:11 a.m.
In 3 patients from 2 Chinese families (an affected father and daughter, and an unrelated Chinese boy) with 'palmoplantar keratoderma and congenital alopecia-1' (PPKCA1; 104100), Wang et al. (2015, PMID:25168385) identified heterozygosity for a c.23G-T missense mutation in the GJA1 gene resulting in a G8V substitution. Patch-clamp studies in transfected HEK293 cells demonstrated a gain-of-function effect.
Created: 9 Jan 2017, 11:10 a.m.
Comment on mode of inheritance: Mode of inheritance sourced from OMIM: monoallelic mutations in GJA1 are recorded for 'Palmoplantar keratoderma with congenital alopecia' (OMIM:104100). Both monoallelic and biallelic mutations in GJA1 are recorded for 'Erythrokeratodermia variabilis et progressiva' (OMIM:133200).
Created: 5 Jan 2017, 12:50 p.m.

Edel O'Toole (Queen Mary University of London)

Green List (high evidence)

Missense mutations, frame-shift and C-terminal truncation reported
Created: 14 Mar 2017, 7 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Erythrokeratoderma; Palmoplantar keratoderma; Oculodentodigital dysplasia; keratoderma, hypotrichosis and leukonychia

Publications

Mode of pathogenicity
Other

Details

Mode of Inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • Other
Phenotypes
  • Palmoplantar keratoderma with congenital alopecia, 104100
  • Erythrokeratodermia variabilis et progressiva 3, 617525
  • Erythrokeratoderma
  • Palmoplantar keratoderma
  • Oculodentodigital dysplasia (ODDD) with palmoplantar keratoderma
  • keratoderma, hypotrichosis and leukonychia
OMIM
121014
Clinvar variants
Variants in GJA1
Penetrance
Complete
Publications
Mode of Pathogenicity
Other - please provide details in the comments
Panels with this gene

History Filter Activity

15 Aug 2017, Gel status: 4

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for GJA1 were set to Palmoplantar keratoderma with congenital alopecia, 104100; Erythrokeratodermia variabilis et progressiva 3, 617525; Erythrokeratoderma; Palmoplantar keratoderma; Oculodentodigital dysplasia (ODDD) with palmoplantar keratoderma; keratoderma, hypotrichosis and leukonychia

11 Apr 2017, Gel status: 4

panel promoted to version 1

Rebecca Foulger (Genomics England curator)

Promoted to Version 1, April 11th 2017: Reviews were assessed, and panel was revised according to expert review and additional curation.

11 Apr 2017, Gel status: 4

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for GJA1 were set to Palmoplantar keratoderma with congenital alopecia, 104100; Erythrokeratodermia variabilis et progressiva, 133200; Erythrokeratoderma; Palmoplantar keratoderma; Oculodentodigital dysplasia (ODDD) with palmoplantar keratoderma; keratoderma, hypotrichosis and leukonychia

16 Mar 2017, Gel status: 4

Gene classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

This gene has been classified as Green List (High Evidence).

16 Mar 2017, Gel status: 4

Set mode of pathogenicity

Rebecca Foulger (Genomics England curator)

Mode of pathogenicity for GJA1 was changed to Other - please provide details in the comments

16 Mar 2017, Gel status: 4

Set mode of pathogenicity

Rebecca Foulger (Genomics England curator)

Mode of pathogenicity for GJA1 was changed to Other - please provide details in the comments

16 Mar 2017, Gel status: 4

Gene classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

This gene has been classified as Green List (High Evidence).

16 Mar 2017, Gel status: 2

Set Mode of Inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for GJA1 was changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal

16 Mar 2017, Gel status: 2

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for GJA1 were set to Palmoplantar keratoderma with congenital alopecia, 104100; Erythrokeratodermia variabilis et progressiva, 133200; Palmoplantar keratoderma with congenital alopecia, 104100; Erythrokeratoderma; Palmoplantar keratoderma; Oculodentodigital dysplasia (ODDD) with palmoplantar keratoderma; keratoderma, hypotrichosis and leukonychia

16 Mar 2017, Gel status: 2

Set publications

Rebecca Foulger (Genomics England curator)

Publications for GJA1 were set to 25398053; 25964267; 25388818; 25168385; 17256797; 16891658

10 Jan 2017, Gel status: 2

Gene classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

This gene has been classified as Amber List (Moderate Evidence).

10 Jan 2017, Gel status: 1

Set Mode of Inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for GJA1 was changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

5 Jan 2017, Gel status: 1

Set Mode of Inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for GJA1 was changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal

5 Jan 2017, Gel status: 1

Added New Source

Rebecca Foulger (Genomics England curator)

GJA1 was added to Palmoplantar keratoderma and erythrokeratodermaspanel. Source: Radboud University Medical Center, Nijmegen

5 Jan 2017, Gel status: 0

Added New Source

Rebecca Foulger (Genomics England curator)

GJA1 was added to Palmoplantar keratoderma and erythrokeratodermaspanel. Sources: Other

5 Jan 2017, Gel status: 0

Created

Rebecca Foulger (Genomics England curator)

GJA1 was created by rfoulger