Early onset or syndromic epilepsy

Gene: ADAM22

Green List (high evidence)

NHSGenomic Medicine Service consideration - the amber rating is appropriate for this gene.

Created: 3 Mar 2022, 5:34 p.m. | Last Modified: 3 Mar 2022, 5:34 p.m.

Panel Version: 2.491

After NHSGenomic Medicine Service consideration, the rating of this gene has not been changed.

Created: 3 Mar 2022, 5:34 p.m. | Last Modified: 3 Mar 2022, 5:34 p.m.

Panel Version: 2.491

Comment on list classification: There is just enough evidence for this gene to be rated GREEN at the next major review, which may make it a borderline case.

Created: 11 Feb 2021, 10:17 a.m. | Last Modified: 11 Feb 2021, 10:18 a.m.

Panel Version: 2.295

Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least two variants reported, in two unrelated cases with biallelic variants together with a knock-in mouse model (Adam22 ΔC5/ΔC5), which has lethal epilepsy, together with other supportive functional studies.

Created: 2 Feb 2021, 12:37 p.m. | Last Modified: 2 Feb 2021, 12:37 p.m.

Panel Version: 2.288

I don't know

Yamagata et al 2019 and Fukata et al, 2021 papers looking at the structural studies of LGI1 and ADAM22; second paper also looking at knock in mouse model.

Created: 27 Jan 2021, 3:16 p.m. | Last Modified: 27 Jan 2021, 3:16 p.m.

Panel Version: 2.274

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Developmental and epileptic encephalopathy 61

Publications

• 31432233
• 33397806

Comment on list classification: Added to panel and rated Amber by Zornitza Stark. 2 families with prominent seizure phenotype and biallelic ADAM22 variants reported (PMIDs:30237576, 27066583). Plus mouse model of seizures. Not yet associated with a disorder in Gene2Phenotype. Amber is appropriate rating awaiting further cases.

Created: 4 May 2020, 4:20 p.m. | Last Modified: 4 May 2020, 4:20 p.m.

Panel Version: 2.47

Mouse model: Adam22-/- mice develop lethal seizures during the first postnatal weeks (e.g. PMID:15876356).

Created: 4 May 2020, 4:18 p.m. | Last Modified: 4 May 2020, 4:18 p.m.

Panel Version: 2.45

PMID:30237576 (Maddirevula et al., 2019) searched their database of clinical exomes for homozygous variants and report an 18 year old male with an Arg860* variant in ADAM22. Seizures started age 5 months with a focal seizure, and continued with generalized tonic clonic seizures and status epilepticus (Supplementary Table). His development was normal until 5 months when he had a slower gain of milestones. He has ID with severely delayed speech. Family history revealed ID and epilepsy in his old brother and in wider family.

Created: 4 May 2020, 4:18 p.m. | Last Modified: 4 May 2020, 4:18 p.m.

Panel Version: 2.44

PMID:27066583. Muona et al., 2016 report a Finnish proband-parent-trio with intractable seizures and ID. Compound het variants c.1202G>A, p.Cys401Tyr and c.2396delG, p.Ser799IlefsTer96 were found in ADAM22. Functional assays showed that mutant proteins failed to form the LGI1-ADAM22 ligand-receptor complex. The variants are unlikely to be full LOF.

Created: 4 May 2020, 4:17 p.m. | Last Modified: 4 May 2020, 4:17 p.m.

Panel Version: 2.44

I don't know

Two families reported; the second one as part of a large consanguineous cohort.
Sources: Expert list

Created: 7 Jan 2020, 3:52 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Epileptic encephalopathy, early infantile, 61, MIM# 617933

Publications

• 27066583
• 30237576