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Intellectual disability

Gene: MAPK8IP3

Green List (high evidence)

MAPK8IP3 (mitogen-activated protein kinase 8 interacting protein 3)
EnsemblGeneIds (GRCh38): ENSG00000138834
EnsemblGeneIds (GRCh37): ENSG00000138834
OMIM: 605431, Gene2Phenotype
MAPK8IP3 is in 4 panels

3 reviews

Eleanor Williams (Genomics England Curator)

Comment on phenotypes: OMIM phenotype recently added to OMIM
Created: 27 Jun 2019, 2 p.m. | Last Modified: 27 Jun 2019, 2 p.m.
Panel Version: 2.898

Ivone Leong (Genomics England Curator)

Comment on list classification: New gene added by external expert and reviewed by curation team: Sufficient evidence has been provided by the external expert review for this gene to be rated green. This gene is not associated with any phenotype on OMIM or Gene2Phenotype.
Created: 18 Feb 2019, 1:49 p.m.

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Platzer et al. (doi.org/10.1016/j.ajhg.2018.12.008 - PMID to be added) report on 13 unrelated individuals with de novo pathogenic variants in MAPK8IP3.

The phenotype consisted - among others - of DD with ID (13/13) as well as variable brain anomalies (incl. cerebral or cerebellar atrophy, corpus callosum anomalies, perisylvian polymicrogyria, etc). Abnormal muscular tone (hypotonia, spasticity or both) was noted in most. Microcephaly, seizures, ataxia, ASD were features seen in fewer individuals.

The variants reported included 2 nonsense, 1 frameshift as well as 6 missense mutations (3 missense variants were found - each - in 2 or more individuals).

All three LoF variants were located in the first exon. (mRNA levels were not studied for these variants although NMD is presumed). The brain anomalies were more consistent for missense variants.

MAPK8IP3 appears intolerant to LoF variants (pLI of 1) with constraint also for missense variants (Z-score of 4.06).

In silico structural modeling was possible for 4 missense variants based on available crystal structures and different mechanisms were presumed (disruption of contacts between Leu444 of adjacent subunits, altered interaction between proximal residues at positions 461 and 466, or disruption of protein protein interactions).

The C.elegans MAPK8IP3 ortholog is encoded by the unc-16 gene. Impaired clearance and accumulation of organelles (incl. lysosomes) in axons is observed in unc-16 mutants (recessive phenotype).

For 6 variants, also conserved in C.elegans, mutants were engineered using CRISPR genome editing. The observed mutant phenotypes (increased axonal lysosomal density compared to controls for 2 variants, sluggish locomotion with lower swimming cycle rate for 1 nonsense and 4 missense variants) were rescued upon CRISPR reverse engineering of each mutant allele back to its wild-type sequence.

The authors cite 3 previous studies, in which individuals investigated for neurodevelopmental disorders where found to harbor de novo MAPK8IP3 variants, namely:
- PMID 25363768 (Iossifov et al.) : p.Tyr94Cys [ASD without ID]
- PMID 28213671 (Berger et al.) : p.Glu461Gly [Smith-Magenis-like phenotype)
- PMID 28135719 (DDD study) p.Arg1146Cys [This variant was found in 3 individuals in the study by Platzer et al.]
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A few additional individuals with neurodevelopmental disorders appear in the denovo-db after filtering for coding variants:
http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=MAPK8IP3
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In ClinVar:
- NM_015133.4:c.111C>G (p.Tyr37Ter) has been submitted by the Undiagnosed Diseases Network (NIH) as likely pathogenic, associated with MAPK8IP3-related disorder (hypotonia, DD, EEG anomalies among the phenotypes). It is not clear whether this subject corresponds to individual #3 reported by the previous study (possibly not the case).
- 2 missense variants [NM_015133.4:c.2447C>A (p.Ala816Asp) / NM_015133.4:c.1288C>T (p.Leu430Phe)] have been submitted as VUS, although the latter was found in an individual with ID (summary evidence tab).
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MAPK8IP3 is not associated with any phenotype in OMIM, nor in G2P.
This gene is not commonly included in gene panels for ID.
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As a result, MAPK8IP3 can be considered for inclusion in this panel as green (rather than amber).
Created: 4 Jan 2019, 3:15 p.m.

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

Phenotypes
Abnormal muscle tone; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
Phenotypes
  • Abnormal muscle tone
  • Global developmental delay
  • Intellectual disability
  • Abnormality of nervous system morphology
  • Neurodevelopmental disorder with or without variable brain abnormalities, 618443
OMIM
605431
Clinvar variants
Variants in MAPK8IP3
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

27 Jun 2019, Gel status: 3

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: MAPK8IP3 were changed from Abnormal muscle tone; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; No OMIM number to Abnormal muscle tone; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Neurodevelopmental disorder with or without variable brain abnormalities, 618443

18 Feb 2019, Gel status: 3

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: mapk8ip3 has been classified as Green List (High Evidence).

18 Feb 2019, Gel status: 0

Set Phenotypes

Ivone Leong (Genomics England Curator)

Phenotypes for gene: MAPK8IP3 were changed from 25363768; 28213671; 28135719 to Abnormal muscle tone; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; No OMIM number

18 Feb 2019, Gel status: 0

Set publications

Ivone Leong (Genomics England Curator)

Publications for gene: MAPK8IP3 were set to

4 Jan 2019, Gel status: 0

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

Konstantinos Varvagiannis (Other)

gene: MAPK8IP3 was added gene: MAPK8IP3 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: MAPK8IP3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: MAPK8IP3 were set to 25363768; 28213671; 28135719 Penetrance for gene: MAPK8IP3 were set to unknown Review for gene: MAPK8IP3 was set to GREEN