The evolving genetic landscape of neuromuscular fetal akinesias

Fetal akinesia is a broad term used to describe absent (or reduced, fetal hypokinesia) fetal movements, and it can be detected as early as the first trimester. Depending on the developmental age of onset, anything that interferes or limits the normal in utero movement results in a range of deformations affecting multiple organs and organ systems. Arthrogryposis, also termed arthrogryposis multiplex congenita (AMC), is a definitive terminology for multiple congenital contractures, with two major subgroups; amyoplasia and distal arthrogryposis (DA). The spectrum includes fetal akinesia deformation sequence (FADS), lethal congenital contracture syndrome (LCCS), and multiple pterygium syndrome (MPS). Variants in more than >400 genes are known to cause AMC, and it is increasingly recognized that variants in genes encoding critical components (including ventral horn cell, peripheral nerve, neuromuscular junction, skeletal muscle) of the extended motor unit underlie ∼40% of presentations. With unbiased screening approaches, including sequencing of comprehensive disease gene panels, exomes and genomes, novel genes and phenotypic expansions associated with known human disease genes have been uncovered in the setting of fetal akinesia. Autosomal-recessive titinopathy is the most frequent genetic cause of AMC. Accurate genetic diagnosis is critical to genetic counseling and informing family planning. Around 50% remain undiagnosed following comprehensive prenatal, diagnostic or research screening. Comprehensive phenotyping and periodic reanalysis with appropriate genomic tools are valuable strategies when faced with initial inconclusive results. There are likely many novel causative genes still to identify, which will inform our understanding of the molecular pathways underlying early human development and in utero movement.