Early onset or syndromic epilepsy

Gene: DPAGT1

Green List (high evidence)

AR congenital myasthenic syndrome with tubular aggregates and AR congenital disorder of glycosylation type Ij. Wurde et al, 2012 - 2 sibs - consang Turkish parents - intractable seizures - death in first year of life - hom DPAGT1 missense variant - RT-PCR analysis showed the mutation increased the amount of normal aberrant splicing in controls , resulting in the skipping of exons 2 & 3 and lead to a truncated protein, in vitro studies done. Iqbal et al, 2013 - Pakistani brother and sister - both develped seizures in childhood - compound het missense variants. Ng et al, 2019 - 14 disease causing mutations in 28 patients from 10 families have prev been reported- in this paper they report another 11 patients from 8 families and add 10 new mutations - approx 50% have epilepsy.

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
Congenital disorder of glycosylation type Ij, 608093; Myasthenic syndrome congenital, 13 with tubular aggregates, 614750

Publications

• 22304930
• 12872255
• 23249953

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: John Taylor and Helen Lord. Suggested gene rating: Green.

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

Panel Version: 1.189

Comment on list classification: Updated rating from Amber to Green: Green review. Confirmed DD-G2P gene for Congenital disorder of glycosylation (CDG), which can present with seizures. Sufficient cases of seizures from the literature (3 cases from PMIDs:22304930, 23249953, 12872255) for inclusion on panel.

Created: 24 Nov 2018, 9:33 p.m.

In a patient with central disorder of glycosylation type Ij, Wu et al. (2003, PMID:12872255) identified reduced DPAGT1 enzymatic activity. In the paternal allele, a variant Y170C was identified. Although no variant was identified in the maternal allele, it produced only 12% of the normal amount of mRNA. She had severe hypotonia and medically intractable seizures amongst her phenotypes.

Created: 24 Nov 2018, 9:22 p.m.

In a Pakistani brother and sister born of unrelated patients with a mild form of CDG Ij, Iqbal et al. (2013, PMID:23249953) identified compound heterozygous mutations in the DPAGT1 gene (I29F and L168P). The patients had normal psychomotor development until ages 2 and 5 years, respectively, when they both developed seizures, hypotonia, and aggressive behavior. Seizures and additional phenotypes continued into adulthood.

Created: 24 Nov 2018, 9:21 p.m.

In 2 sibs, born of consanguineous Turkish parents, with severe CDG Ij, Wurde et al. 2012 (PMID:22304930) identified a homozygous mutation in the DPAGT1 gene (p.A114G). The patients had a severe form which included intractable seizures, and died within the first year of life.

Created: 24 Nov 2018, 9:19 p.m.

Green List (high evidence)

Seizures are a feature of this multi system metabolic disorder.

Created: 12 Aug 2018, 6:52 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Congenital disorder of glycosylation, type Ij, MIM#608093

Variants in this GENE are reported as part of current diagnostic practice