Syndromic craniosynostosis caused by a novel missense variant in MAP4K4: Expanding the genotype-phenotype...

RASopathies represent a distinct class of neurodevelopmental syndromes caused by germline variants in the Ras/MAPK pathways. Recently, a novel disease-gene association was implicated in MAPK kinase kinase kinase 4 (MAP4K4), which regulates the upstream signals of the MAPK pathways. However, to our knowledge, only two studies have reported the genotype-phenotype relationships in the MAP4K4-related disorder. This study reports on a Korean boy harboring a novel de novo missense variant in MAP4K4 (NM_001242559:c.569G>T, p.Gly190Val), revealed by trio exome sequencing, and located in the hotspot of the protein kinase domain. The patient exhibited various clinical features, including craniofacial dysmorphism, language delay, congenital heart defects, genitourinary anomalies, and sagittal craniosynostosis. Our study expands the phenotypic association of the MAP4K4-related disorder to include syndromic craniosynostosis, thereby providing further insights into the role of the RAS/MAPK pathways in the development of premature fusion of calvarial sutures.