Heterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly.
Charlotte HerbstViktoria BotheMeret WeglerSusanne Axer-SchaeferSéverine Audebert-BellangerJozef GeczBenjamin CogneHagit Baris FeldmanAnselm H C HornAnna C E HurstMelissa A KellyMichael C KruerAlina KurolapAnnie LaquerriereMegan LiPaul R MarkMarkus MorawskiMathilde NizonTomi PastinenTilman PolsterPascale Saugier-VeberJang SeSongHeinrich StichtJens T StielerIsabelle ThifffaultClare L van EykPascale MarcorellesMyriam Vezain-MouchardRami Abou JamraHenry OppermannPublished in: Human genetics (2024)
Neurons form the basic anatomical and functional structure of the nervous system, and defects in neuronal differentiation or formation of neurites are associated with various psychiatric and neurodevelopmental disorders. Dynamic changes in the cytoskeleton are essential for this process, which is, inter alia, controlled by the dedicator of cytokinesis 4 (DOCK4) through the activation of RAC1. Here, we clinically describe 7 individuals (6 males and one female) with variants in DOCK4 and overlapping phenotype of mild to severe global developmental delay. Additional symptoms include coordination or gait abnormalities, microcephaly, nonspecific brain malformations, hypotonia and seizures. Four individuals carry missense variants (three of them detected de novo) and three individuals carry null variants (two of them maternally inherited). Molecular modeling of the heterozygous missense variants suggests that the majority of them affect the globular structure of DOCK4. In vitro functional expression studies in transfected Neuro-2A cells showed that all missense variants impaired neurite outgrowth. Furthermore, Dock4 knockout Neuro-2A cells also exhibited defects in promoting neurite outgrowth. Our results, including clinical, molecular and functional data, suggest that loss-of-function variants in DOCK4 probable cause a variable spectrum of a novel neurodevelopmental disorder with microcephaly.
Keyphrases
- copy number
- intellectual disability
- zika virus
- induced apoptosis
- early onset
- poor prognosis
- cell proliferation
- multiple sclerosis
- spinal cord
- cell death
- genome wide
- spinal cord injury
- oxidative stress
- gene expression
- blood brain barrier
- physical activity
- signaling pathway
- functional connectivity
- dna methylation
- big data
- congenital heart disease
- single molecule
- resting state
- cerebral ischemia
- electronic health record
- white matter
- case control