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Genetic epilepsy syndromes

Gene: AP2M1

Green List (high evidence)

AP2M1 (adaptor related protein complex 2 mu 1 subunit)
EnsemblGeneIds (GRCh38): ENSG00000161203
EnsemblGeneIds (GRCh37): ENSG00000161203
OMIM: 601024, Gene2Phenotype
AP2M1 is in 4 panels

4 reviews

Rebecca Foulger (Genomics England curator)

I don't know

Kept rating as Green based on Green post-Webex review from Helen Lord.
Created: 9 Sep 2019, 10:11 a.m. | Last Modified: 9 Sep 2019, 10:11 a.m.
Panel Version: 1.310
Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.
Panel Version: 1.262

Helen Lord (Oxford Medical Genetics Laboratories)

Green List (high evidence)

AD epilepsy - not in OMIM. Helbig et al, 2019 (31104773) - de novo variant detected in 2 individuals with a similar phenotype including epilepsy with myoclonic atonic seizures. This variant was then detected in 2 other unrelated individuals who had generalised epilepsy and functional work support pathogenicity of this variant. Of note the only reported variant is a recurrent de novo missense variant p.Arg170Trp.
Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.
Panel Version: 1.261

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

Mode of pathogenicity
Other

Catherine Snow (Genomics England)

Green List (high evidence)

Comment on mode of pathogenicity: Currently only one missense variant identified in all four cases. If this remains the case we would want to whitelist this variant in future rather than calling all variants in this gene.
Created: 9 Jul 2019, 8:37 a.m. | Last Modified: 9 Jul 2019, 8:37 a.m.
Panel Version: 0.65
Advice from the clinical team - "In view of four cases with the same variant and phenotype, supported by some evidence of altered gene function, I think this meets our criteria for inclusion." There was also concern that this was not a Founder effect, however the individuals were from very separate populations.
Created: 9 Jul 2019, 8:31 a.m. | Last Modified: 9 Jul 2019, 8:31 a.m.
Panel Version: 0.63
Expert review by Konstantinos Varvagiannis on AP2M1. Helbig et al. (2019 - PMID: 31104773) report on 4 individuals with developmental and epileptic encephalopathy due to a recurrent de novo AP2M1 missense variant (NM_004068.3:c.508C>T or p.Arg170Trp). As this single publication reports on one amino acid variant, requesting support from the Genomics England Clinical Team as to whether this should be Green in both the ID panel (panel 285) and Genetic Epilepsy Syndromes panel (panel 402).
Created: 24 Jun 2019, 4:08 p.m. | Last Modified: 24 Jun 2019, 4:08 p.m.
Panel Version: 0.6

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Helbig et al. (2019 - PMID: 31104773) report on 4 individuals with developmental and epileptic encephalopathy due to a recurrent de novo AP2M1 missense variant (NM_004068.3:c.508C>T or p.Arg170Trp). Seizure types included atonic, myoclonic-atonic, absence seizures (with or without eyelid myoclonia), tonic-clonic etc. Hypotonia, developmental delay (prior to the onset of seizures at 1y 3m to 4y) and intellectual disability were observed in all four. Other features included ataxia (3/4) or autism spectrum disorder (2/4).

AP2M1 encodes the μ-subunit of the adaptor protein complex 2 (AP-2). AP2M1 is highly expressed in the CNS. The AP-2 complex is involved in clathrin-mediated endocytosis at the plasma mebrane of neurons and non-neuronal cells. This mechanism is important for recycling synaptic vesicle components at mammalian central synapses. Previous evidence suggests regulation of GABA and/or glutamate receptors at the neuronal surface by AP-2 (several references provided by Helbig et al.).

The authors provide evidence for impaired (reduced) clathrin-mediated endocytosis of transferrin in AP-2μ-depleted human HeLa cells upon plasmid-based re-expression of the Arg170Trp variant compaired to re-expression of WT. A similar defect was demonstrated upon comparison of the same process when WT and Arg170Trp re-expression was studied in primary astrocytes from conditional AP-2μ knockout mice.

Expression levels, protein stability, membrane recruitment and localization of the AP-2 complex in clathrin-coated pits were similar for the Arg170Trp variant and WT. As a result, the effect of the specific variant is suggested to be mediated by alteration of the AP-2 complex function (/impaired recognition of cargo membrane proteins) rather than haploinsufficiency.

AP2M1 is highly intolerant to missense / LoF variants with z-score and pLI in ExAC of 5.82 and 0.99 respectively.

As the authors discuss, heterozygous Ap2m1 mutant mice do not have an apparent phenotype. Homozygous mutant mice die before day 3.5 postcoitus, suggesting a critical role in early embryonic development (PMID 16227583 cited)

AP2M1 is currently not associated with any phenotype in OMIM / G2P.

As a result, this gene can be considered for inclusion in the epilepsy and ID panels probably as green (4 individuals with highly similar phenotype of DEE, relevance of phenotype and/or degree of ID, functional studies, etc) rather than amber (single recurrent variant - although this is also the case for other genes rated green).
Sources: Literature
Created: 31 May 2019, 7:06 p.m.

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

Phenotypes
Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Ataxia; Autistic behavior

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review
  • Expert Review Green
  • Expert Review Green
  • Expert Review
Phenotypes
  • Intellectual developmental disorder 60 with seizures, 618587
  • Seizures
  • Ataxia
  • Generalized hypotonia
  • Intellectual disability
  • Global developmental delay
  • Autistic behavior
Tags
missense
OMIM
601024
Clinvar variants
Variants in AP2M1
Penetrance
Complete
Publications
Mode of Pathogenicity
Other
Panels with this gene

History Filter Activity

3 Oct 2019, Gel status: 3

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: AP2M1 were changed from Seizures; Ataxia; Generalized hypotonia; Intellectual disability; Global developmental delay; Autistic behavior to Intellectual developmental disorder 60 with seizures, 618587; Seizures; Ataxia; Generalized hypotonia; Intellectual disability; Global developmental delay; Autistic behavior

17 Sep 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to AP2M1.

17 Sep 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to AP2M1.

9 Sep 2019, Gel status: 3

Set mode of pathogenicity

Rebecca Foulger (Genomics England curator)

Mode of pathogenicity for gene: AP2M1 was changed from Other to Other

29 Jul 2019, Gel status: 3

Added Tag

Catherine Snow (Genomics England)

Tag missense tag was added to gene: AP2M1.

22 Jul 2019, Gel status: 3

Added New Source, Added New Source, Set mode of pathogenicity, Set Phenotypes, Status Update

Catherine Snow (Genomics England)

Source Expert Review Green was added to AP2M1. Source Expert Review was added to AP2M1. Mode of pathogenicity for gene AP2M1 was changed from None to Other Added phenotypes Seizures; Ataxia; Generalized hypotonia; Intellectual disability; Global developmental delay; Autistic behavior for gene: AP2M1 Rating Changed from No List (delete) to Green List (high evidence)

31 May 2019, Gel status: 0

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

Konstantinos Varvagiannis (Other)

gene: AP2M1 was added gene: AP2M1 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: AP2M1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: AP2M1 were set to 31104773 Phenotypes for gene: AP2M1 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Ataxia; Autistic behavior Penetrance for gene: AP2M1 were set to Complete Review for gene: AP2M1 was set to GREEN