Consolidating the Association of Biallelicmapkapk5pathogenic Variants with a Distinct Syndromic Neurodevelopmental Disorder

BackgroundMAPK-activated protein kinase 5 (MAPKAPK5) is an essential enzyme for diverse cellular processes. Dysregulation of the pathways regulated by MAPKAPK enzymes can lead to the development of variable diseases. Recently, homozygous loss-of-function variants inMAPKAPK5were reported in four patients from three families presenting with a recognisable neurodevelopmental disorder, so-called ‘neurocardiofaciodigital’ syndrome.Objective and methodsIn order to improve characterisation of the clinical features associated with biallelicMAPKAPK5variants, we employed a genotype-first approach combined with reverse deep-phenotyping of three affected individuals.ResultsIn the present study, we identified biallelic loss-of-function and missenseMAPKAPK5variants in three unrelated individuals from consanguineous families. All affected individuals exhibited a syndromic neurodevelopmental disorder characterised by severe global developmental delay, intellectual disability, characteristic facial morphology, brachycephaly, digital anomalies, hair and nail defects and neuroradiological findings, including cerebellar hypoplasia and hypomyelination, as well as variable vision and hearing impairment. Additional features include failure to thrive, hypotonia, microcephaly and genitourinary anomalies without any reported congenital heart disease.ConclusionIn this study, we consolidate the causality of loss of MAPKAPK5 function and further delineate the molecular and phenotypic spectrum associated with this new ultra-rare neurodevelopmental syndrome.