Growth failure in early childhood
Gene: MAPK1After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains AMBERCreated: 31 Jan 2023, 5:28 p.m. | Last Modified: 31 Jan 2023, 5:28 p.m.
Panel Version: 2.33
Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype (probable). There is enough evidence to support a gene-disease association; however, the patients in the article did not meet the criteria set out for this panel. However, will check with the Genomics England Clinical Team. Therefore, this gene has been given an Amber rating until further confirmation.Created: 30 Sep 2021, 1:15 p.m. | Last Modified: 30 Sep 2021, 1:15 p.m.
Panel Version: 1.75
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).
Sources: Expert ReviewCreated: 18 Aug 2021, 9:50 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Noonan syndrome 13, MIM#619087
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
Tag Q4_21_expert_review was removed from gene: MAPK1. Tag Q4_21_rating was removed from gene: MAPK1. Tag Q4_21_phenotype was removed from gene: MAPK1.
Tag Q4_21_rating tag was added to gene: MAPK1.
Tag Q4_21_expert_review tag was added to gene: MAPK1. Tag Q4_21_phenotype tag was added to gene: MAPK1.
Gene: mapk1 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: MAPK1 were changed from Noonan syndrome 13, MIM#619087 to Noonan syndrome 13, OMIM:619087
gene: MAPK1 was added gene: MAPK1 was added to Growth failure in early childhood. Sources: Expert Review Mode of inheritance for gene: MAPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MAPK1 were set to 32721402 Phenotypes for gene: MAPK1 were set to Noonan syndrome 13, MIM#619087 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