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Intellectual disability

Gene: NEMF

Amber List (moderate evidence)

NEMF (nuclear export mediator factor)
EnsemblGeneIds (GRCh38): ENSG00000165525
EnsemblGeneIds (GRCh37): ENSG00000165525
OMIM: 608378, Gene2Phenotype
NEMF is in 2 panels

2 reviews

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

Comment on list classification: Rating Amber but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag)
Created: 3 Nov 2020, 11:45 a.m. | Last Modified: 3 Nov 2020, 11:45 a.m.
Panel Version: 3.507
Comment on mode of inheritance: Set MOI to 'Biallelic' as currently only 1 case (total 14) with a monoallelic variant described but with normal intellectual development.
Created: 3 Nov 2020, 11:42 a.m. | Last Modified: 3 Nov 2020, 11:42 a.m.
Panel Version: 3.505
At least 14 unrelated families reported with variants in NEMF (13 biallelic, 1 monoallelic). GDD/ID is reported in all but 2 cases (USA1 and USA3 in PMID: 32934225) albeit mostly within the mild range. Nonetheless, there are sufficient cases with moderate-severe ID to warrant a Green rating on this panel. Some cases also do not present all other features associated with NEMF variants (e.g. neuropathy) providing further support for inclusion.
Created: 3 Nov 2020, 11:35 a.m. | Last Modified: 3 Nov 2020, 11:35 a.m.
Panel Version: 3.504
Currently not associated with any phenotype in OMIM (last edited on 04/01/2017) or Gene2Phenotype.

- PMID: 33048237 (2020) - 13 affected individuals from 5 unrelated families presenting with a spectrum of central (speech delay (12/13), intellectual disability (13/13), abnormal eye movement, scoliosis) and peripheral (axonal neuropathy, lower limb hypotonia) neurological involvement. Degree of ID was mild to moderate in families 1-4, while the patient in family 5 displayed severe cognitive delay. Knockdown studies in cultured mouse primary cortical neurons showed a significant decrease in axon length and impaired synapse development.

PMID: 27431290 (2017) - 3 individuals from 2 unrelated families with different homozygous truncating variants in NEMF and non-syndromic ID. Assessment of the two sibs indicated severe ID. Details are limited regarding the other individual but developmental delay was noted with an inability to speak at 4 years.
Created: 3 Nov 2020, 11:14 a.m. | Last Modified: 3 Nov 2020, 11:14 a.m.
Panel Version: 3.504

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could not be ruled out that a de novo and maternally inherited variant were on the same allele, as phase was not determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides produced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration in mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Sources: Literature
Created: 3 Oct 2020, 8:16 p.m. | Last Modified: 3 Oct 2020, 8:31 p.m.
Panel Version: 3.369

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Hypotonia; Global developmental delay; Intellectual disability; Axonal neuropathy; Ataxia; Abnormal brain imaging; Kyphosis; Scoliosis; Tremor; Respiratory distress

Publications

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
Phenotypes
  • Hypotonia
  • Global developmental delay
  • Intellectual disability
  • Axonal neuropathy
  • Ataxia
  • Abnormal brain imaging
  • Kyphosis
  • Scoliosis
  • Tremor
  • Respiratory distress
Tags
for-review
OMIM
608378
Clinvar variants
Variants in NEMF
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

3 Nov 2020, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

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

3 Nov 2020, Gel status: 0

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: NEMF were set to 32934225

3 Nov 2020, Gel status: 0

Set mode of inheritance

Arina Puzriakova (Genomics England Curator)

Mode of inheritance for gene: NEMF was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal

3 Nov 2020, Gel status: 0

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag for-review tag was added to gene: NEMF.

3 Oct 2020, Gel status: 0

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

Konstantinos Varvagiannis (Other)

gene: NEMF was added gene: NEMF was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: NEMF was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: NEMF were set to 32934225 Phenotypes for gene: NEMF were set to Hypotonia; Global developmental delay; Intellectual disability; Axonal neuropathy; Ataxia; Abnormal brain imaging; Kyphosis; Scoliosis; Tremor; Respiratory distress Penetrance for gene: NEMF were set to Complete Review for gene: NEMF was set to GREEN