Early onset or syndromic epilepsy

Gene: GRIN1

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

Green List (high evidence)

AD (NDHMSD) or AR (NDHMSR) neurodevelopmental disorder with or without hyperkinetic movements and seizures. On OMIM variable seizures seen in some patients. NDHMSD - Hamdan et al, 2011 - 2 unrelated patients, no epilepsy - de novo het mutations a missense variant and a single AA dup, functional studies done. Ohba et al, 2015 - 4 unrelated patients - onset of seizures in first year of life - 4 diff de novo het missense mutations - no functional studies. Lemke et al, 2016 - 14 unrelated patients and reevaluated 9 prev reported patients (total 23) - 70% had epilepsy - variability in type. 22/23 variants de novo and parental DNA available for other. 16 diff mutations - all missense mutations clustered within or in close proximity to the transmemb domains, functional work done - support pathogenicity. Chen et al, 2017 - 2 unrelated patients - no seizures- 2 diff de novo het mutations resulting in same AA substitution, in vitro studies support pathogenicity. NDHMSR - Lemke et al, 2016 - 2 bothers consang parents - no seizures - hom missense variant, carrier parents unaffected and functional studies support pathogenicity. In addition 3 sibs born of consang parents with severe neonatal epilepsy - seizures day 1 of life and died very young - hom nonsense variant - functional studies showed the mutation rendered the channel non-functional, het carrier parents unaffected. Rossi et al, 2017 - 2 sibs of consng Moroccan patients - no seizures - hom missense variant, carrier parents not affected no functional work done.

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

Panel Version: 1.188

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder with or without hyperkinetic movements and seizures,614254; Neurodevelopmental disorder with or without hyperkinetic movements and seizures,617820

Publications

• 27164704

Comment on publications: Added publications to support the MOI. For NDHMSR, to date there are three unrelated consanguineous families with NDHMSR in the literature, Lemke et al. (2016) PMID: 27164704 and Rossi et al. (2017) PMID:28051072.
For NDHMSD to date there are 16 unrelated cases with NDHMSD in the literature, Lemke et al. (2016) PMID: 27164704 (a re-evaluation of some previous cases and new cases with NDHMSD) and Chen et al. (2017) PMID: 28228639

Created: 4 Feb 2018, 4:41 p.m.

Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant (NDHMSD) is a severe neurodevelopmental disorder characterized by profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, and a hyperkinetic movement disorder. Additional features may include cortical blindness, generalized cerebral atrophy, and seizures (summary by Lemke et al., 2016). To date, there are 16 unrelated cases with NDHMSD in the literature, Lemke et al. (2016) PMID: 27164704 (a re-evaluation of some previous cases and new cases with NDHMSD) and Chen et al. (2017) PMID: 28228639.
Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive (NDHMSR) is an autosomal recessive neurodevelopmental disorder characterized by severely delayed psychomotor development, severe intellectual disability, and involuntary movements, including stereotypic movements, spasticity, and dystonia. Affected individuals are are usually unable to walk independently and have poor or absent speech. Some patients have intractable seizures (summary by Lemke et al., 2016). The transmission pattern of NDHMSR in the families reported by Lemke et al. (2016) was consistent with autosomal recessive inheritance. PMID: 27164704. To date there are three unrelated consanguineous families with NDHMSR in the literature, Lemke et al. (2016) PMID: 27164704 and Rossi et al. (2017) PMID:28051072.

Created: 4 Feb 2018, 4:37 p.m.

Comment on phenotypes: added new phenotypes from OMIM update

Created: 4 Feb 2018, 4:33 p.m.

Comment on publications: added new publications

Created: 4 Feb 2018, 4:21 p.m.

Comment on mode of inheritance: PMID: 27164704 (2017) evidence for both monoallelic and biallelic inheritance for Neurodevelopmental disorder with or without hyperkinetic movements and seizures.

Created: 4 Feb 2018, 4:19 p.m.

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

• Ohba et al (2015) Epilepsia doi: 10.1111/epi.12987

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

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

• Ohba et al (2015) Epilepsia doi: 10.1111/epi.12987

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

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

• Ohba et al (2015) Epilepsia doi: 10.1111/epi.12987

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

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

• Ohba et al (2015) Epilepsia doi: 10.1111/epi.12987

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

Comment on phenotypes: Sources: OMIM, PMID: 25864721, G2P.

Created: 5 Jan 2016, 12:13 p.m.

Comment when marking as ready: 4 reviewers agree this gene should be rated green for this gene panel and provide a study reporting GRIN1 mutations in 4 out of 88 patients with unclassified early onset epileptic encephalopathies. It is a "possible DD gene" for epileptic encephalopathy on G2P.

Created: 5 Jan 2016, 12:12 p.m.

Comment on mode of inheritance: Checked the imprinted gene list.

Created: 5 Jan 2016, 12:07 p.m.

Gene added in expert review of the panel by Richard Scott (Genomics England), Manju Kurian (UCL-Institute of Child Health), Natalie Trump (NHS - Great Ormond Street Hospital), Amy McTague (UCL Institute of Child Health).

Created: 12 Nov 2015, 4:14 p.m.