Intellectual disability
Gene: NECAP1

NECAP1 (NECAP endocytosis associated 1)
EnsemblGeneIds (GRCh38): ENSG00000089818
EnsemblGeneIds (GRCh37): ENSG00000089818
OMIM: 611623, Gene2Phenotype
NECAP1 is in 2 panels

2 reviews

Ivone Leong (Genomics England Curator)

Comment on list classification: New gene added by external expert and reviewed by curation team. NECAP1 has been given an amber gene rating based on the evidence provided by Konstantinos Varvagiannis. As patients from the cases described in PMID: 24399846, 30525121 are from Saudi Arabia and have the same variant, these are counted as a single piece of evidence. Therefore, there are not enough evidence to promote this gene to a green rating at this stage.
Created: 20 Feb 2019, 4:14 p.m.

Created: 20 Feb 2019, 4:14 p.m.

Panel version: 2.689

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Biallelic pathogenic variants in NECAP1 cause ?Epileptic encephalopathy, early infantile, 21 (MIM 615833).
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PMID: 24399846 (Alazami et al. 2014) report on 6 individuals from an multigenerational family from Saudi Arabia with biallelic NECAP1 nonsense variant. The common phenotype consisted of hypotonia, profound global developmental delay preceding the onset of intractable seizures (fragmented multifocal clonic and tonic) in early infancy. Initial workup excluded metabolic causes.

4 of these individuals were born to first cousins once removed, while 2 additional affected subjects from the broader pedigree were born to seemingly unrelated parents from the same region. All affected individuals shared a single autozygous 4.78-Mb interval on chromosome 12p. Linkage analysis confirmed involvement of this locus (LOD score : 5.0447). Exome sequencing demonstrated homozygosity for a nonsense variant (NM_015509.3:c.142C>T - p.R48*). mRNA levels in lymphoblast cell lines from affected subjects were significantly reduced when compared to controls, probably due to NMD.

Necap1 was shown to be strongly expressed in the developing (E14.5) mouse brain and spinal cord, upon immunohistochemical analysis (part of the current study).

NECAP1 has been previously shown to have a functional role in Clathrin-mediated encocytocis (CME), a process which plays a critical role at the site of synapsis (in synaptic vesicle recycling).
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PMID: 30525121 (Alsahli et al. 2018) report on a 41-month-old girl with hypotonia, profound global developmental delay and onset of seizures at the age of 3 months (generalized tonic and clonic / flexor hemispasms). Initial workup was negative for an eventual metabolic origin. The girl was born to consanguineous Saudi parents and was found to harbor the p.R48* variant in the homozygous state, following trio-WES.
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PMID: 30626896 (Mizuguchi et al. 2019) report on a 16-month-old boy, born to consanguineous parents from Malaysia. This individual presented with axial hypotonia and profound developmental delay and developed generalized tonic-clonic and clonic seizures at the (corrected) age of 3 months. EEG demonstrated a burst suppression pattern and a clinical diagnosis of Ohtahara syndrome was retained. Metabolic workup was normal.

Homozygosity for a splice-site NECAP1 variant (NM_015509.3:c.301+1G>A) was demonstrated following exome sequencing. The variant was shown to result in inclusion of a 44-bp intron, resulting in frameshift and introduction of a premature termination codon (p.Gly101Aspfs*45). The level of abnormal transcript was 2-fold increased in lymphoblast cells trated with cycloheximide when compared to cells treated with DMSO, suggesting involvement of NMD.

As also in PMID: 30525121, the present study suggests similarities with the DNM1-related phenotype (Epileptic encephalopathy, early infantile, 31 - #616346 - DNM1 is rated green in the ID panel) as DNM1 also participates in vesicle recycling. The authors of the present study also note that mutations in CLTC (encoding clathrin heavy chain) cause hypotonia with DD/ID with or without epilepsy (Mental retardation, autosomal dominant 56 - #617854 - CLTC is rated green in the ID panel).
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NECAP1 is not associated with any phenotype in G2P.
This gene is included in gene panels for ID offered by some diagnostic laboratories.
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As a result this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature
Created: 3 Feb 2019, 8 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Epileptic encephalopathy, early infantile 21, 615833

Publications

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

Created: 3 Feb 2019, 8 p.m.

Panel version: 2.621

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Amber

Phenotypes

?Epileptic encephalopathy, early infantile 21, 615833

OMIM

611623

Clinvar variants

Variants in NECAP1

Penetrance

Complete

Publications

Panels with this gene

History Filter Activity

20 Feb 2019, Gel status: 2

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: necap1 has been classified as Amber List (Moderate Evidence).

3 Feb 2019, Gel status: 0

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

Konstantinos Varvagiannis (Other)

gene: NECAP1 was added gene: NECAP1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: NECAP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NECAP1 were set to 24399846; 30525121; 30626896 Phenotypes for gene: NECAP1 were set to ?Epileptic encephalopathy, early infantile 21, 615833 Penetrance for gene: NECAP1 were set to Complete Review for gene: NECAP1 was set to GREEN gene: NECAP1 was marked as current diagnostic

Intellectual disability Gene: NECAP1