Early onset or syndromic epilepsy

Gene: CCDC88A

Comment on list classification: There are now at least 7 individuals from 4 unrelated families with biallelic variants in the CCDC88A gene (PMID: 26917597; 30392057; 37798908; 39334473), described to a PEHO-like syndrome with universal features including ID, epilepsy, microcephaly and optic nerve/cerebellar atrophy.

Sufficient unrelated cases with the same phenotype to promote this gene to green at the next GMS panel update.

Created: 6 Nov 2024, 4:24 p.m. | Last Modified: 6 Nov 2024, 4:24 p.m.

Panel Version: 7.4

Green List (high evidence)

Four families with biallelic variants and PEHO-like (progressive encephalopathy with edema, hypsarrhythmia and optic atrophy) phenotype reported in the literature.

Created: 29 Oct 2024, 10:44 a.m. | Last Modified: 29 Oct 2024, 10:44 a.m.

Panel Version: 6.15

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 39334473
• 37798908
• 26917597

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: Alison Callaway and John Taylor. Suggested gene rating: Amber.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

I don't know

insufficient families.Two consanguinous families identified with PEHO, PMID 26917597,30392057. Otherwise limited information.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?PEHO syndrome-like, 617507

Publications

• 26917597

I don't know

As suggested in previous reviews this gene should possibly remain amber based on PMID: 26917597 (3 individuals from a broader consanguineous pedigree, all homozygous for a nonsense variant shown to escape NMD but producing a severely truncated protein. Mouse knockout phenotype mimics the human).

PMID: 30392057 is probably a second report on the phenotype related to biallelic CCDC88A mutations. 2 sibs born to consanguineous parents from Saudi Arabia are described very briefly (epilepsy, ID, optic atrophy and pedal edema). Both sibs were homozygous for a novel truncating variant [c.1292G>A p.(Trp431*)].

NB. Apart from the poor phenotypic description the article has a few additional issues :
- The reference sequence is not mentioned but c.1292G>A would correspond to Trp431* whether NM_001135597/NM_018084/NM_001254943 is used [http://www.mutationtaster.org/cgi-bin/MutationTaster/MT_ChrPos.cgi?chromosome=2&position=55570825&ref=C&alt=T] The sequence from the chromatograms provided maps only to CCDC88A and corresponds to the predicted amino acid change (using UCSC's Blat).
- The 3 additional variants in Table 1 (ref: Ekici et al. 2010) probably correspond to CCDC88C but not CCDC88A [correct reference for these variants : Ekici et al., 2010 - PMID: 21031079].

The corresponding phenotype in OMIM is # 617507 PEHO-like syndrome.

Created: 19 Nov 2018, 1:47 p.m.

Publications

• 26917597
• 30392057

Green List (high evidence)

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

Created: 24 Feb 2025, 5:59 p.m. | Last Modified: 24 Feb 2025, 5:59 p.m.

Panel Version: 7.39

Comment when marking as ready: Insufficient evidence at present for gene to be green (13/11/2018)

Created: 13 Nov 2018, 10:27 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

I don't know

Single family reported with three affected siblings with bi-allelic variants in this gene and early onset severe seizures. Mouse model provides supportive evidence, however does not meet criteria for Green.

Created: 10 Aug 2018, 4:29 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
PEHO syndrome-like, MIM#617507

Publications

• 26917597