Likely inborn error of metabolism

Gene: NUS1

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.

Created: 4 May 2024, 3:17 p.m. | Last Modified: 4 May 2024, 3:17 p.m.

Panel Version: 5.3

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Green List (high evidence)

Comment on list classification: As there is sufficient evidence available for the association of monoallelic NUS1 variants with intellectual disability and epilepsy, this gene can be promoted to green rating in the next GMS review.

Created: 5 Jan 2024, 7:43 p.m. | Last Modified: 5 Jan 2024, 7:43 p.m.

Panel Version: 4.95

Comment on mode of inheritance: As reviewed by Dmitrijs Rots, there are more than three unrelated cases and functional evidence available in support of the association of monoallelic NUS1 variants with intellectual disability and epilepsy. This autosomal dominant disorder has been recorded in both OMIM (MIM #617831) and Gene2Phenotype (with 'strong' rating in the DD panel).

However, there is only one family and supporting functional evidence available for the association of biallelic variants with congenital disorder of glycosylation. This phenotype has already been recorded in OMIM (MIM #617082), but not in Gene2Phenotype.

Hence, the MOI should be updated from 'BIALLELIC, autosomal or pseudoautosomal' to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted'.

Created: 5 Jan 2024, 7:40 p.m. | Last Modified: 5 Jan 2024, 7:40 p.m.

Panel Version: 4.94

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Intellectual developmental disorder, autosomal dominant 55, with seizures, OMIM:617831; ?Congenital disorder of glycosylation, type 1aa, OMIM:617082

Green List (high evidence)

Multiple patients (see below) with de novo or heterozygous variants reported. The phenotype include ID, seizures and/or movement disorder (including tremor, ataxia, dystonia). Functional analysis of patients fibroblasts shows"de novo NUS1 variants reduce NgBR and Niemann–Pick type C2 (NPC2) protein amount, impair dolichol biosynthesis, and cause lysosomal cholesterol accumulation." (Yu et al,m 2021). Movement abnormalities and similar metabolic dysfunction in zebrafish model.

3 patients reported in: PMID: 33731878
One patient reported in: PMID: 32334381
One family reported in: PMID: 32485575
Two cases reported in: PMID: 31656175

Additionally, two cases from one family with homozygous missense variant is reported:PMID: 25066056
Metabolic defect include:"fibroblasts isolated from patients exhibit reduced dolichol profiles and enhanced accumulation of free cholesterol identically to fibroblasts from mice lacking NgBR", which seems to be in line with effect of dominant variants described above.

Created: 27 Jun 2021, 2:44 p.m. | Last Modified: 27 Jun 2021, 2:44 p.m.

Panel Version: 2.143

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
intellectual disability; seizures; ataxia; tremor; dystonia

Publications

• PMID: 33731878
• 32334381
• 32485575
• 31656175
• 25066056

I don't know

Comment on list classification: Promoting from red to amber on advice from Genomics England clinical team. 1 case plus some functional data.

Created: 12 Jan 2021, 11:15 p.m. | Last Modified: 12 Jan 2021, 11:15 p.m.

Panel Version: 2.44

Provisionally associated with ?Congenital disorder of glycosylation, type 1aa #617082 (AR) in OMIM based on family reported in Park et al 2014 (PMID: 25066056). They describe a family of Roma origin in which 2 out of 4 siblings presented with congenital scoliosis, severe neurological impairment, refractory epilepsy, hearing deficit and visual impairment with discrete bilateral macular lesions. A homozgyous missense mutation, R290H, was found in NUS1 (called NGBR in the paper) by exome sequencing. It segregated with the disease in the family. Patient fibroblasts showed reduced dolichol profiles and enhanced accumulation of free cholesterol as do fibroblasts from mice lacking NgBR.

Created: 12 Jan 2021, 11:11 p.m. | Last Modified: 12 Jan 2021, 11:11 p.m.

Panel Version: 2.41

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Congenital disorder of glycosylation, type 1aa OMIM:617082; congenital disorder of glycosylation, type IAA MONDO:0014904

Publications

• 25066056