Early onset or syndromic epilepsy

Gene: NSF

I don't know

PMID:36645181 describes the two previously reported cases from PMID:31675180. The third case reported had a very mild phenotype and did not present with epilepsy and had normal development. Hence, this gene should remain AMBER.

This gene has now been associated with relevant phenotype in OMIM (MIM #619340), but not in Gene2Phenotype.

Created: 17 May 2023, 10:19 a.m. | Last Modified: 17 May 2023, 10:20 a.m.

Panel Version: 4.37

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Developmental and epileptic encephalopathy 96, OMIM:619340

Publications

• 36645181

I don't know

Not associated with relevant phenotype in OMIM or Gen2Phen (11/05/2021). At least two variants reported in two unrelated cases with epileptic encephalopathy of early infantile onset, one proband died at day 36 after birth of respirative failure, the other proband has profound intellectual disability, severe motor developmental delay, and no spontaneous respiration. Supportive functional studies in Drosophila were also presented (PMID 31675180).

Created: 11 May 2021, 6:15 p.m. | Last Modified: 11 May 2021, 6:15 p.m.

Panel Version: 2.345

I don't know

Two unrelated individuals with de novo missense variants.

Created: 5 Feb 2020, 4:59 a.m. | Last Modified: 5 Feb 2020, 4:59 a.m.

Panel Version: 2.0

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Seizures; EEG with burst suppression; Global developmental delay; Intellectual disability

Publications

• 31675180

I don't know

Suzuki et al. (2019 - PMID: 31675180) report on 2 unrelated individuals with de novo missense NSF variants. Overall the phenotype corresponded to an early infantile epileptic encephalopathy. The first patient developed vomiting and tonic seizures immediately after birth, with burst-suppression pattern upon EEG. Trio exome sequencing, followed by Sanger sequencing of proband and parents, revealed a de novo missense variant (NM_006178.3:c.1375G>A / p.Ala459Thr), absent from public databases and predicted in silico to be deleterious (CADD score of 30). The girl died 36 days after birth due to respiratory failure. Another subject, having necessitated mechanical ventilation due to absence of spontaneous respiration after birth, developed myoclonic seizures. EEG showed a burst-suppression pattern. At the age of 3, she was noted to have persistence of seizures and profound ID. Trio exome sequencing identified a missense NSF variant (c.1688C>T / p.Pro563Leu) also confirmed and shown to be de novo by Sanger sequencing. Again the variant was absent from public datasets and had a CADD score of 34. While expression of wt NSF allele in the developing eye of Drosophila had no effect, expression of mutants severely affected eye development - suggesting a dominant negative effect. NSF encodes a homo-hexameric AAA ATPase, which is recruited by SNAPs (Soluble NSF Attachment Proteins) - and the latter by SNAREs (SNAP REceptors) - thus having a role in vesicular transport and membrane fusion. There is currently no associated phenotype in OMIM/G2P. Overall, this gene could be considered for inclusion probably with amber/red rating pending further evidence (eg. additional work-up or alternative causes/explanations not discussed).
Sources: Literature

Created: 11 Nov 2019, 5:39 p.m.

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

Phenotypes
Seizures; EEG with burst suppression; Global developmental delay; Intellectual disability

Publications

• 31675180