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Intellectual disability

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 3 panels

3 reviews

Ellen McDonagh (Genomics England Curator)

I don't know

As this single publication reports on one amino acid variant, I would request a second opinion from Richard Scott in 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: 17 Jun 2019, 8:26 a.m.

Catherine Snow (Genomics England)

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, 8:39 a.m. | Last Modified: 9 Jul 2019, 8:39 a.m.
Panel Version: 0.199
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, 8:38 a.m. | Last Modified: 9 Jul 2019, 8:38 a.m.
Panel Version: 0.197
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). 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.

Initial two individuals identified by a semantic similarity analysis of phenotypic features in their cohort of 314 individuals with DEEs. Two additional individuals with the same AP2M1 de novo variant were identified when querying a diagnostic cohort of 2,310 epilepsy-affected individuals who had undergone WES.

Although a single variant, there are sufficient cases of ID/DD, from unrelated individuals to warrant a Green rating for AP2M1.
Created: 13 Jun 2019, 9:56 a.m.

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, 7:03 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
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

29 Jul 2019, Gel status: 3

Added Tag

Catherine Snow (Genomics England)

Tag missense tag was added to gene: AP2M1.

25 Jul 2019, Gel status: 3

Added New Source, Added New Source, Set Phenotypes, Status Update

Catherine Snow (Genomics England)

Source Expert Review Green was added to AP2M1. Source Expert Review was added to AP2M1. 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 Intellectual disability. 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