TY - JOUR
T1 - Biallelic truncating variants in MAPKAPK5 cause a new developmental disorder involving neurological, cardiac, and facial anomalies combined with synpolydactyly
AU - Horn, Denise
AU - Fernández-Núñez, Elisa
AU - Gomez-Carmona, Ricardo
AU - Rivera-Barahona, Ana
AU - Nevado, Julian
AU - Schwartzmann, Sarina
AU - Ehmke, Nadja
AU - Lapunzina, Pablo
AU - Otaify, Ghada A.
AU - Temtamy, Samia
AU - Aglan, Mona
AU - Boschann, Felix
AU - Ruiz-Perez, Victor L.
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.
PY - 2021/4
Y1 - 2021/4
N2 - Purpose: This study aimed to identify the genetic cause of a new multiple congenital anomalies syndrome observed in three individuals from two unrelated families. Methods: 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. Results: 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. Conclusion: 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.
AB - Purpose: This study aimed to identify the genetic cause of a new multiple congenital anomalies syndrome observed in three individuals from two unrelated families. Methods: 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. Results: 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. Conclusion: 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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U2 - 10.1038/s41436-020-01052-2
DO - 10.1038/s41436-020-01052-2
M3 - Article
C2 - 33442026
AN - SCOPUS:85099380412
SN - 1098-3600
VL - 23
SP - 679
EP - 688
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 4
ER -