Palmoplantar keratoderma and erythrokeratodermas
Gene: GJA1Comment on mode of inheritance: MOI was set to 'both mono- and biallelic' in 2017 as PPK has been observed in some patients with oculodentodigital dysplasia (ODDD). Although GJA1-related ODDD can be dominantly (MIM:164200) or recessively (MIM:257850) inherited, of the 4 unrelated families published to date with confirmed recessive ODDD (PMID: 14981729, 16816024, 20597923, 29902798) none have reported dermal abnormalities. It is possible that these may have been overlooked in the context of other more prominent features of the disorder - but this further emphasises the limited value of this panel for this particular phenotype.
MOI for GJA1 on the GMS Palmoplantar keratodermas (R166) panel was set to 'monoallelic' in 2019, and so the MOI was also updated to 'monoallelic' on this panel to reflect this.
Notably, heterozygous variants are also associated with other relevant phenotypes (MIM: 617525 & 104100)Created: 31 Aug 2021, 2:11 p.m. | Last Modified: 31 Aug 2021, 3:57 p.m.
Panel Version: 1.20
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.
Missense mutations, frame-shift and C-terminal truncation reportedCreated: 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
Mode of inheritance for gene: GJA1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Tag Q3_21_MOI was removed from gene: GJA1. Tag Q3_21_expert_review was removed from gene: GJA1.
Tag Q3_21_MOI tag was added to gene: GJA1. Tag Q3_21_expert_review tag was added to gene: GJA1.
Mode of inheritance for gene: GJA1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: GJA1 were changed from 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 to Erythrokeratodermia variabilis et progressiva 3, OMIM:617525; Palmoplantar keratoderma with congenital alopecia, OMIM:104100; Oculodentodigital dysplasia, OMIM:164200
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
Promoted to Version 1, April 11th 2017: Reviews were assessed, and panel was revised according to expert review and additional curation.
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
This gene has been classified as Green List (High Evidence).
Mode of pathogenicity for GJA1 was changed to Other - please provide details in the comments
Mode of pathogenicity for GJA1 was changed to Other - please provide details in the comments
This gene has been classified as Green List (High Evidence).
Mode of inheritance for GJA1 was changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
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
Publications for GJA1 were set to 25398053; 25964267; 25388818; 25168385; 17256797; 16891658
This gene has been classified as Amber List (Moderate Evidence).
Mode of inheritance for GJA1 was changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mode of inheritance for GJA1 was changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
GJA1 was added to Palmoplantar keratoderma and erythrokeratodermaspanel. Source: Radboud University Medical Center, Nijmegen
GJA1 was added to Palmoplantar keratoderma and erythrokeratodermaspanel. Sources: Other
GJA1 was created by rfoulger