Arthrogryposis

Gene: SCN1A

The rating of this gene has been updated following NHS Genomic Medicine Service approval

Created: 3 Mar 2022, 3:49 p.m. | Last Modified: 3 Mar 2022, 3:49 p.m.

Panel Version: 3.150

Green List (high evidence)

Note we have reported this association previously in PMID 29543227 (Supplementary info) in an infant presenting with AMC and severe EE, and de novo p.(Ile1347Asn) variant which at the time was thought to only partially explain the phenotype, but in light of this new report, likely fully explains the phenotype. Given the presence of severe seizure disorder in the two infants who were phenotyped in the newborn period, this likely represents the severe end of the spectrum of SCN1A-related disorders rather than a distinct association.

Created: 2 Oct 2020, 10:17 p.m. | Last Modified: 2 Oct 2020, 10:17 p.m.

Panel Version: 3.13

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Arthrogryposis multiplex congenita; Dravet syndrome, MIM# 607208

Publications

• 32928894
• 29543227

I don't know

Comment on list classification: There are sufficient unrelated cases (4) reported in 2 papers (PMIDs: 32928894 and 29543227) with ACM and variants in this gene.

It is anticipated that early-onset seizures likely represent the predominant feature of the disease presentation (already Green on the Genetic epilepsy syndromes panel), however this gene will be flagged for review to assess whether inclusion on this panel is likely to be of clinical benefit.

Created: 2 Dec 2020, 2:44 p.m. | Last Modified: 2 Dec 2020, 2:44 p.m.

Panel Version: 3.18

Note SCN1A is a well-established cause of Dravet syndrome, MIM# 607208

Created: 2 Oct 2020, 4:09 p.m. | Last Modified: 2 Oct 2020, 4:09 p.m.

Panel Version: 3.13

Comment on list classification: Association with this phenotype currently based on a single publication, although reporting 3 unrelated cases.

Rating Amber, awaiting further publications/clinical evidence to validate this gene-disease relationship.

Created: 2 Oct 2020, 4:05 p.m. | Last Modified: 2 Oct 2020, 4:05 p.m.

Panel Version: 3.13

PMID: 32928894 (2020) - De novo missense variants in SCN1A (p.Leu893Phe, p.Ala989Thr, p.Ile236Thr) were identified in three unrelated patients with AMC which was diagnosed from the second trimester of pregnancy. One patient developed intractable epilepsy from birth and died at 21 days, while the other two pregnancies were terminated. No functional studies of the variants or patient cells were performed.
Sources: Literature

Created: 2 Oct 2020, 4 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Arthrogryposis multiplex congenita

Publications

• 32928894