Early onset or syndromic epilepsy

Gene: ABCA2

I don't know

Hu et al, 2019 - Supp document M8600615 - 3 sibs with an ABCA2 variant - only III2 had a history of seizures - controlled by medication; Aslam and Naz 2019 - neither of these sibs with a ABCA2 variant had seizures - also in table 1 it references the patient reported in Steinberg et al 2015 - no seizures mentioned, and Maddirevula et al 2019 - 2 unrelated individuals who had a phenptype of ID dev delay and epilepsy (Supp table has clinical info). Don't think there is enough cases/functional work to make this to support green rating.

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

Panel Version: 2.274

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
intellectual delay, poor growth, ataxia, seizures

Publications

• 29302074
• 31047799
• 30237576

I don't know

Comment on list classification: Rating Amber as 1) only 2 cases with seizures; 2) epilepsy is not a prominent feature of the overall phenotype; 3) seizures were either resolved or managed by medication.

Created: 16 Nov 2020, 12:58 p.m. | Last Modified: 16 Nov 2020, 12:58 p.m.

Panel Version: 2.212

Associated with relevant phenotype in OMIM, but currently not in Gene2Phenotype.

At least 7 individuals from 4 unrelated families reported at present with different biallelic variants in the ABCA2 gene. Overlapping clinical features include psychomotor delay (6/7), microcephaly (3/7), ataxia (3/7), and epilepsy (2/7). Of those with seizures, epilepsy was resolved in one patient and the other was controlled by medication.

Created: 16 Nov 2020, 11:41 a.m. | Last Modified: 16 Nov 2020, 11:41 a.m.

Panel Version: 2.211

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Intellectual developmental disorder with poor growth and with or without seizures or ataxia, OMIM: 618808

Publications

• 30237576
• 29302074
• 31047799

Green List (high evidence)

Biallelic pathogenic ABCA2 variants cause Intellectual developmental disorder with poor growth and with or without seizures or ataxia (MIM 618808).

There are 3 relevant publications (01-07-2020) :
- Maddirevula et al [2019 - PMID: 30237576] described briefly 2 unrelated subjects (16-2987, 16DG0071) both DD and seizures among other manifestations.
- Hu et al [2019 - PMID: 29302074] reported 3 sibs (M8600615 - III:1-3) born to consanguineous parents (M8600615 - III:1-3) with DD/ID (formal confirmation of moderate ID, in those (2) evaluated). One also presented with seizures.
- Aslam and Naz [2019 - PMID: 31047799] provided clinical details on 2 siblings born to consanguineous parents. ID was reported for the older sib but was absent in the younger one. Seizures were not part of the phenotype.

All subjects harbored biallelic pLoF variants.

N.B. : Steinberg et al [2015 - PMID: 25773295], within a cohort of patients with ALS, identified one with biallelic ABCA2 variants. As however Aslam and Naz comment, this person harbored a single pathogenic variant, with a second one rather unlikely to be pathogenic due to high allele frequency.

Overall this gene can be considered for inclusion with green rating in both ID and epilepsy panels (each in >=3 unrelated individuals).
Sources: Literature

Created: 13 Jul 2020, 6:25 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Intellectual developmental disorder with poor growth and with or without seizures or ataxia, 618808

Publications

• 30237576
• 29302074
• 31047799