Early onset or syndromic epilepsy

Gene: VPS11

I don't know

Kept rating as Green based on Green post-Webex review from Helen Lord.

Created: 9 Sep 2019, 10:47 a.m. | Last Modified: 9 Sep 2019, 10:47 a.m.

Panel Version: 1.321

Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

Green List (high evidence)

AR HLD12. Edvardson et al, 2015 (26307567) - 8 patients from 4 unrelated famiies of AJ descent with dev delay assoc with hypomyelination on brain imaging, 3 patients had rare and well-controlled partial seizures. A hom missense variant C846G was identifed. In vitro functional studies indicated that the mutation resulted in a defect in the fusion of the late endosome to the vacuole. Zhang et al, 2016 (27120463) - 5 patients from 3 unrelated families of AJ descent - all have seizures. C846G idenitifed in all.Haplotype analysis indicated a founder effect. Expersssion of the mutation in HeLa cells showed that it has decreased stability compared to wt, this was assoc with increased ubiquitination of the mutant protein resulting in significantly decreased protein levels. Hortnagel et al, 2016 (27473128) - 2 siblings with a similar phenptype one of whom died aged 16 and the other aged 16 months. The elder had seizures noted from 1 year of age. Both had a hom inframe del of 2AA. Parents both het carriers.

Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.

Panel Version: 1.261

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

Comment on list classification: Gene identified by an expert review by Konstantinos Varvagiannis. PMIDs: 27120463 and 26307567 report on 13 individuals from 7 Ashkenazi families, all with the same variant, therefore reported as a founder effect.
Seizures are seen in 3 individuals from the 8 reported in PMID:26307567 and in PMID: 27120463 all 5 of the individuals are reported to have seizures.

A second different variant (p.Leu387_Gly395del) of VPS11 was found in the homozygous state in 2 sibs born to consanguineous parents of a Turkish origin (PMID: 27473128).

VPS11 is in OMIM and seizures are noted in the phenotypes. VPS11 can be classified as Green, as a second variant unrelated to the founder effect has been identified.

Created: 25 Jun 2019, 3:18 p.m. | Last Modified: 15 Jul 2019, 1:46 p.m.

Panel Version: 0.74

Green List (high evidence)

Biallelic mutations in VPS11 cause Leukodystrophy, hypomyelinating, 12 (MIM 616683).

PMIDs: 27120463, 26307567, 27473128 all report on this disorder.

The phenotype consists of global DD, ID, (variable) acquired microcephaly with hypomyelination upon brain MRI. Seizures appear to be a feature in several individuals.

Almost all individuals appear to be of Ashkenazi Jewish descent, homozygous for a founder mutation (NM_021729.5:c.2536T>G or p.Cys846Gly). PMIDs: 27120463 and 26307567 report on 13 individuals from 7 Ashkenazi families.

A second variant (p.Leu387_Gly395del) was however found in the homozygous state in 2 sibs born to consanguineous parents. Seizures were also noted in both.

Pathogenicity is supported by extensive functional studies in all relevant articles.

VPS11 is not associated with any phenotype in G2P.

As a result, this gene can be considered for inclusion in this panel probably as green (or amber).

[Please consider inclusion in the lysosomal disorders panel as well as in the undiagnosed metabolic disorders panel].
Sources: Literature

Created: 14 Dec 2018, 4:07 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Leukodystrophy, hypomyelinating, 12 (MIM 616683)

Publications

• 27120463
• 26307567
• 27473128