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Genetic epilepsy syndromes

Gene: NUS1

Green List (high evidence)

NUS1 (NUS1 dehydrodolichyl diphosphate synthase subunit)
EnsemblGeneIds (GRCh38): ENSG00000153989
EnsemblGeneIds (GRCh37): ENSG00000153989
OMIM: 610463, Gene2Phenotype
NUS1 is in 6 panels

3 reviews

Rebecca Foulger (Genomics England curator)

I don't know

Updated rating from Amber to Green based on Green post-Webex review from Helen Lord. Also updated MOI from 'monoallelic' to 'BOTH monoallelic and biallelic' based on Helen's review.
Created: 9 Sep 2019, 11:09 a.m. | Last Modified: 9 Sep 2019, 11:09 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

Helen Lord (Oxford Medical Genetics Laboratories)

Green List (high evidence)

AR CDG1AA. Park et al, 2014 (25066056) - 2 sibs born of unrelated Czech parents both had early onset refractory seizures. Hom missense variant identifed (R290H), parents het carriers. Functional studies support pathogenicity. 16 other missense variants reported on HGMD Pro - de novo het variants in NUS1 contributing to Parkinson's disease (Guo et al, 2018 (30348779)). Hamden et al, 2018 (29100083) - supp table - DEE patients - indvKW - male with global dev delay , mod ID and seizures from 12 months - de novo fs variant in NUS1; HSJ0623 - presented at 10 months of age with seizures and mild motor delay - de novo fs variant in NUS1; HSJ0627 - presented at 2.5 years with seizures - de novo intragenic deletion of ~1.3kb in exon 2 of NUS1.
Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.
Panel Version: 1.261

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Eleanor Williams (Genomics England Curator)

I don't know

Comment on mode of inheritance: A single family with a biallelic pattern is also reported. Further cases advised to confirm MOI.
Created: 28 Feb 2019, 10:39 a.m.
Following review by the Genomics England clinical team it was decided to rate this gene amber on the Genetic epilepsy syndromes panel at this time. Evidence is most compelling for an epilepsy phenotype associated with heterozygous LOF de novo variants at present.
Created: 28 Feb 2019, 10:39 a.m.
NUS1 is associated with Mental retardation, autosomal dominant 55, with seizures (AD inheritance) and ?Congenital disorder of glycosylation, type 1aa (AR inheritance) in OMIM. It is associated with Epilepsy and intellectual disability in Gene2Phenotype (probable) with monoallelic inheritance.

PMID: 25066056 (Park et al 2014) - 2 sibs, born of unrelated Czech parents of Roma descent, with congenital disorder of glycosylation type Iaa - a homozygous missense mutation in the NUS1 gene (p.Arg290His (R290H), which is located in the evolutionarily conserved C-terminal domain of NgBR) . The siblings presented with congenital scoliosis, severe neurological impairment, refractory epilepsy, hearing deficit and visual impairment with discrete bilateral macular lesions. Functional studies with WT and mutant fibroblasts show that fibroblasts isolated from patients exhibit reduced dolichol profiles and enhanced accumulation of free cholesterol identically to fibroblasts from mice lacking NgBR.

PMID: 29100083 (Hamdan et al 2017) - performed whole-genome sequencing (WGS) on 197 developmental and epileptic encephalopathy individuals and their unaffected parents. 3 unrelated individuals identified with de novo changes in NUS1 - p.Asp248Alafs), p.Val48Profs)∗7, exon 2 deletion. All had seizures and mild to severe ID.
Created: 28 Feb 2019, 10:37 a.m.
Adding NUS1 to this panel following review of the gene by Konstantinos Varvagiannis on the Intellectual Disability panel https://panelapp.genomicsengland.co.uk/panels/285/gene/NUS1/.
Sources: Expert Review
Created: 28 Feb 2019, 10:36 a.m.

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

Phenotypes
#617082 - ?Congenital disorder of glycosylation, type 1aa; #617831 - Mental retardation, autosomal dominant 55, with seizures; Abnormality of extrapyramidal motor function

Publications

Details

Mode of Inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Wessex and West Midlands GLH
  • NHS GMS
  • Expert Review Green
  • Expert Review
Phenotypes
  • ?Congenital disorder of glycosylation, type 1aa, 617082
  • Mental retardation, autosomal dominant 55, with seizures, 617831
  • Abnormality of extrapyramidal motor function
OMIM
610463
Clinvar variants
Variants in NUS1
Penetrance
None
Publications
Panels with this gene

History Filter Activity

17 Sep 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to NUS1.

17 Sep 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to NUS1.

9 Sep 2019, Gel status: 3

Set mode of inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for gene: NUS1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal

9 Sep 2019, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: nus1 has been classified as Green List (High Evidence).

9 Sep 2019, Gel status: 2

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: NUS1 were changed from #617082 - ?Congenital disorder of glycosylation, type 1aa; #617831 - Mental retardation, autosomal dominant 55, with seizures; Abnormality of extrapyramidal motor function to ?Congenital disorder of glycosylation, type 1aa, 617082; Mental retardation, autosomal dominant 55, with seizures, 617831; Abnormality of extrapyramidal motor function

28 Feb 2019, Gel status: 2

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: nus1 has been classified as Amber List (Moderate Evidence).

28 Feb 2019, Gel status: 1

Set mode of inheritance

Eleanor Williams (Genomics England Curator)

Mode of inheritance for gene: NUS1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

28 Feb 2019, Gel status: 1

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Eleanor Williams (Genomics England Curator)

gene: NUS1 was added gene: NUS1 was added to Genetic epilepsy syndromes. Sources: Expert Review Mode of inheritance for gene: NUS1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: NUS1 were set to 25066056; 29100083; 24824130; 30348779 Phenotypes for gene: NUS1 were set to #617082 - ?Congenital disorder of glycosylation, type 1aa; #617831 - Mental retardation, autosomal dominant 55, with seizures; Abnormality of extrapyramidal motor function Review for gene: NUS1 was set to AMBER