Early onset or syndromic epilepsy

Gene: PLXNA1

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.

Created: 11 Oct 2023, noon | Last Modified: 11 Oct 2023, noon

Panel Version: 4.110

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Green List (high evidence)

Comment on list classification: There is sufficient evidence (five unrelated cases) available for associating monoallelic variants in this gene with epilepsy/ seizures with a GREEN rating and hence this gene can be promoted at the next major review.

Created: 2 May 2023, 4:33 p.m. | Last Modified: 2 May 2023, 4:33 p.m.

Panel Version: 4.20

Monoallelic cases:

PMID:28464511 reported a male patient with a de novo variant in PLXNA1 and presenting with intractable infantile onset epilepsy, and intellectual disability with autism spectrum disorder. In addition, this patient also had features suggestive of Dubowitz syndrome, including growth failure, dermatologic symptoms, and characteristic dysmorphic facial features. It has also been reviewed in this publication that one of only two previously reported cases with missense PLXNA1 variants had epileptic encephalopathy.

PMID:34054129 reported ten cases from seven families with PLXNA1 variants. Of these cases, three unrelated cases had monoallelic de novo variants and presented with global developmental delay, seizures and craniofacial, brain and eye anomalies.


Biallelic cases:

Out of ten cases reported in PMID:34054129, seven cases from four unrelated families exhibited biallelic variants in PLXNA1 gene. They presented with global developmental delay and craniofacial, brain and eye anomalies. However, seizures are not reported in biallelic cases except one family (15 episodes of febrile and nonfebrile seizures reported in family A).

The biallelic variants in this gene has been associated with phenotypes in OMIM (MIM #619955). However, both monoalellic and biallelic variants in this gene has been associated with phenotypes in Gene2Phenotype (with 'limited' rating).

Functional studies:

Structural modeling of missense variants in PLXNA1 suggests distortion in the native protein. Knockdown of plxna1a leads to cerebral anomalies and eye anomalies in zebrafish larvae.
Sources: Literature

Created: 2 May 2023, 4:29 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
developmental and epileptic encephalopathy, MONDO:0100062

Publications

• 28464511
• 34054129