Limb disorders

Gene: MAPKAPK5

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 25 Feb 2025, 9:05 a.m. | Last Modified: 25 Feb 2025, 9:05 a.m.

Panel Version: 6.10

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

Comment on list classification: As there is sufficient evidence available (6 unrelated families), this gene can be promoted to green rating in the next GMS update.

Created: 24 Jul 2024, 11:40 a.m. | Last Modified: 24 Jul 2024, 11:40 a.m.

Panel Version: 5.7

PMID:35575217 reported a 19-month-old boy of Italian descent with neurocardiofaciodigital syndrome (NCFD). He had global developmental delay and his digit abnormalities include short fingers, broad big toes and marked toenail hypoplasia/dysplasia. He was identified with a pathogenic homozygous nonsense variant in MAPKAPK5 gene (p.Arg394Ter).

PMID:36581449 reported three unrelated individuals (one each from Pakistani, Palestinian - Arab and Egyptian descent) with NCFD. All of them had varying degrees of developmental delay and intellectual disability (one each with profound, severe and moderate ID), and digit abnormalities. They were all identified with homozygous MAPKAPK5 variant (p.Leu224Cysfs*4, p.Gln437Ter and p.Gly107Val ).

This gene has been associated with relevant phenotypes in OMIM (MIM #619869) and Gene2Phenotype (with 'strong' rating on the DD panel).

Created: 24 Jul 2024, 11:36 a.m. | Last Modified: 24 Jul 2024, 11:45 a.m.

Panel Version: 5.7

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurocardiofaciodigital syndrome, OMIM:619869

Publications

• 35575217
• 36581449

I don't know

MAPKAPK5 is not yet associated with any phenotype in OMIM (last edited on 06/04/2016) but has a 'probable' disease confidence rating for 'MAPKAPK5-associated syndrome with synpolydactyly' in Gene2Phenotype.

- PMID: 33442026 (2021) - 3 individuals from 2 families with severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with an additional hypoplastic digit between the fourth and fifth digits of hands and/or feet. Exome sequencing identified different homozygous truncating variants in MAPKAPK5 in both families, segregating with disease and unaffected parents as carriers.

Patient-derived cells showed no expression of MAPKAPK5 protein isoforms and reduced levels of the MAPKAPK5-interacting protein ERK3. F-actin recovery after latrunculin B treatment was found to be less efficient in patient-derived fibroblasts than in control cells, supporting a role of MAPKAPK5 in F-actin polymerization.

Rating Amber, awaiting further cases.
Sources: Literature

Created: 30 Apr 2021, 9:27 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Developmental delay, variable brain anomalies, congenital heart defects, dysmorphism; Synpolydactyly

Publications

• 33442026