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Intellectual disability

Gene: MAPK1

Amber List (moderate evidence)

MAPK1 (mitogen-activated protein kinase 1)
EnsemblGeneIds (GRCh38): ENSG00000100030
EnsemblGeneIds (GRCh37): ENSG00000100030
OMIM: 176948, Gene2Phenotype
MAPK1 is in 2 panels

2 reviews

Catherine Snow (Genomics England)

Green List (high evidence)

Expert review on MAPK1 from Konstantinos Varvagiannis on Motta et al (2020 - PMID: 32721402)
Motta et al reports on 7 unrelated individuals who all have missense MAPK1 variants.
GoF mechanism suggested and supported by in silico/vitro/vivo studies including knock out MAPK1 C. elegans studies.
Phenotype relevant for this panel to rate as Green
Created: 19 Nov 2020, 2:39 p.m. | Last Modified: 19 Nov 2020, 2:39 p.m.
Panel Version: 3.553

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

Phenotypes
Noonan syndrome 13, OMIM:619087; MONDO:0018997

Publications

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Motta et al (2020 - PMID: 32721402) report on 7 unrelated individuals harboring de novo missense MAPK1 pathogenic variants.

The phenotype corresponded to a neurodevelopmental disorder and - as the authors comment - consistently included DD, ID , behavioral problems. Postnatal growth delay was observed in approximately half. Hypertelorism, ptosis, downslant of palpebral fissures, wide nasal bridge as low-set/posteriorly rotated ears were among the facial features observed (each in 3 or more subjects within this cohort). Together with short/webbed neck and abnormalities of skin (lentigines / CAL spots) and growth delay these led to clinical suspicion of Noonan s. or disorder of the same pathway in some. Congenital heart defects (ASD, mitral valve insufficiency, though not cardiomyopathy) occurred in 4/7. Bleeding diathesis and lymphedema were reported only once.

MAPK1 encodes the mitogen-activated protein kinase 1 (also known as ERK2) a serine/threonine kinase of the RAS-RAF-MEK-(MAPK/)ERK pathway.

MAPK1 de novo variants were identified in all individuals following trio exome sequencing (and extensive previous genetic investigations which were non-diagnostic).

The distribution of variants, as well as in silico/vitro/vivo studies suggest a GoF effect (boosted signal through the MAPK cascade. MAPK signaling also upregulated in Noonan syndrome).

The authors comment that screening of 267 additional individuals with suspected RASopathy (without mutations in previously implicated genes) did not reveal other MAPK1 variants.

Overall this gene can be considered for inclusion in the ID panel with green rating.
Sources: Literature
Created: 1 Aug 2020, 12:14 a.m.

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

Phenotypes
Global developmental delay; Intellectual disability; Behavioral abnormality; Growth delay; Abnormality of the face; Abnormality of the neck; Abnormality of the cardiovascular system; Abnormality of the skin

Publications

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
Phenotypes
  • Global developmental delay
  • Intellectual disability
  • Behavioral abnormality
  • Growth delay
  • Abnormality of the face
  • Abnormality of the neck
  • Abnormality of the cardiovascular system
  • Abnormality of the skin
Tags
for-review
OMIM
176948
Clinvar variants
Variants in MAPK1
Penetrance
unknown
Publications
Mode of Pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Panels with this gene

History Filter Activity

19 Nov 2020, Gel status: 2

Added Tag

Catherine Snow (Genomics England)

Tag for-review tag was added to gene: MAPK1.

19 Nov 2020, Gel status: 2

Entity classified by Genomics England curator

Catherine Snow (Genomics England)

Gene: mapk1 has been classified as Amber List (Moderate Evidence).

1 Aug 2020, Gel status: 0

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

Konstantinos Varvagiannis (Other)

gene: MAPK1 was added gene: MAPK1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: MAPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MAPK1 were set to 32721402 Phenotypes for gene: MAPK1 were set to Global developmental delay; Intellectual disability; Behavioral abnormality; Growth delay; Abnormality of the face; Abnormality of the neck; Abnormality of the cardiovascular system; Abnormality of the skin Penetrance for gene: MAPK1 were set to unknown Mode of pathogenicity for gene: MAPK1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: MAPK1 was set to GREEN