Biallelic truncating variants in MAPKAPK5 cause a new developmental disorder involving neurological, cardiac, and facial anomalies combined with synpolydactyly



This study aimed to identify the genetic cause of a new multiple congenital anomalies syndrome observed in three individuals from two unrelated families.


Clinical assessment was conducted prenatally and at different postnatal stages. Genetic studies included exome sequencing (ES) combined with single-nucleotide polymorphism (SNP) array based homozygosity mapping and trio ES. Dermal fibroblasts were used for functional assays.


A clinically recognizable syndrome characterized by 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 was identified. Additional features included eye abnormalities, hearing impairment, and electroencephalogram anomalies. ES detected different homozygous truncating variants in MAPKAPK5 in both families. 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.


Our data indicate that loss-of-function variants in MAPKAPK5 result in a severe developmental disorder and reveal a major role of this gene in human brain, heart, and limb development.

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Fig. 1: Clinical features of individuals with biallelic pathogenic variants in MAPKAPK5.
Fig. 2: Description of the variants identified in MAPKAPK5 and their effect on MK5 and ERK3 expression.
Fig. 3: Loss of MK5 impairs F-actin cytoskeleton recovery.
Fig. 4: F-actin/G-actin quantification in primary fibroblasts.

Data availability

Data supporting this paper are contained within the article and Supplementary information. Any additional data not compromised by ethical issues will be available upon request.


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We are grateful to patients and their parents for their participation in this study. The work at IIB was financially supported by the Spanish Ministry of Science, Innovation and Universities (PID2019-105620RB-I00/AEI/10.13039/501100011033 and SAF2016‐75434‐R (AEI/FEDER, UE). The authors also acknowledge the GeneMatcher tool30 which allowed the identification of these two families and Manuel Holtgrewe, Core Unit Bioinformatics of the Berlin Institute of Health (BIH), for processing of the exome data of family 2.

Author information




Conceptualization: D.H., F.B., S.T., G.A.O., M.A., P.L., V.L.R.-P. Funding acquisition: V.L.R.-P. Formal analysis: E.F.-N., A.R.-B., N.E. Investigation: E.F.-N., R.G.-C., A.R.-B., J.N., V.L.R.-P., N.E., F.B. Project administration: P.L., V.L.R.-P. Resources: D.H., F.B., M.A., S.T., G.A.O., S.S. Supervision: D.H., F.B., S.T., M.A., V.L.R.-P. Visualization: E.F.-N., A.R.-B., G.A.O., M.A., D.H., F.B., V.L.R.-P. Writing—original draft: D.H., F.B., M.A., S.T., G.A.O., P.L., V.L.R.-P. Writing—review & editing: D.H., S.S., N.E., F.B., E.F.-N., A.R.-B., P.L., G.A.O., S.T., M.A., V.L.R.-P.

Corresponding authors

Correspondence to Denise Horn or Victor L. Ruiz-Perez.

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Ethics Declaration

Parental consent was obtained for all clinical and molecular studies of this report and for the publication of clinical photographs. All studies and investigations were performed according to the declaration of Helsinki principles of medical research involving human subjects and the study was approved by institutional Ethics Committees of National Research Centre, Hospital La Paz-CSIC and Charité-Universitaetsmedizin (EA2/140/17).

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The authors declare no competing interests.

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Horn, D., Fernández-Núñez, E., Gomez-Carmona, R. et al. Biallelic truncating variants in MAPKAPK5 cause a new developmental disorder involving neurological, cardiac, and facial anomalies combined with synpolydactyly. Genet Med (2021).

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