Early onset or syndromic epilepsy

Gene: NECAP1

I don't know

Mitochondrial disorders can associated with seizures, but the evidence is not specifically implicated. There are reports of disease-causing variants being associated with complex I deficiency. There is a case report of two brothers with complex I/Leigh syndrome and generalised tonic-clonic seizures, PMID 17275378.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Epileptic encephalopathy, early infantile, 21, 615833

Publications

• 24399846

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: Alison Callaway and John Taylor. Suggested gene rating: Amber.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Comment on mode of inheritance: Set MOI to BIALLELIC to match reviews by Konstantinos and Zornitza, recent papers and OMIM.

Created: 16 May 2019, 4 p.m.

PMID:30626896 (Mizuguchi et al. 2019) report a 16-month-old Malaysian boy who developed infantile-onset tonic-clonic and tonic seizures age 3 months, then spasms in clusters. WES identified the splice site variant c.301+1G>A in NECAP1.

Created: 16 May 2019, 3:59 p.m.

PMID:30525121 (Alsahli et al. 2018) report a second Saudi family that is not related to the family in PMID:24399846 (Alazami et al., 2014) but harbours the same homozygous R48X variant, and the authors suggest a Saudi founder variant. The proband is 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).

Created: 16 May 2019, 3:59 p.m.

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.
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As a result this gene can possibly be considered for upgrade in this panel to green.

Created: 3 Feb 2019, 8:02 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Epileptic encephalopathy, early infantile 21, 615833

Publications

• 24399846
• 30525121
• 30626896

Comment when marking as ready: Single family reported.

Created: 11 Dec 2018, 1:13 p.m.

Red List (low evidence)

Single family reported.

Created: 17 Aug 2018, 10:36 a.m.

Single family reported.

Created: 17 Aug 2018, 10:35 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Epileptic encephalopathy, early infantile, 21, MIM#615833

Publications

• 24399846

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)