Multiomics Approach Reveal Novel Insights in FUS Driven Juvenile Amyotrophic Lateral Sclerosis: A Family Quartet Analysis

Background Juvenile amyotrophic lateral sclerosis (JALS) is a rare and severe form of motor neuron disease characterized by progressive loss of upper and lower motor neurons with an early onset (<25 years). Purpose Due to complex etiology and clinical heterogeneity, it is indispensable to unravel molecular mechanisms underlying JALS pathology. The study aimed to identify disease-specific signatures in a 14-years-old sporadic JALS patient. Methods Genomic, transcriptomic, and metabolomic analysis of proband and first-degree relatives (FDR). Results Exome sequencing identified a novel de novo frameshift variation (c.1465dupG: p.D490Gfs*26) in the fused in sarcoma (FUS) gene in proband. Interestingly, rare and potentially deleterious, disease-modifying variations in DDHD domain containing 1 (DDHD1) and fibrillin 2 (FBN2) were observed. Differentially expressed genes (DGEs) enriched in neuromuscular transmission and inflammatory response were identified by RNA-sequencing. In addition, alterations in purine and pyrimidine, vitamin B6, and sphingolipid metabolism reflect the involvement of inflammatory process in disease pathobiology. Conclusion Our findings suggest the involvement of multiple genetic factors coupled with hampered neuromuscular transmission and systemic inflammation in the onset and disease course of JALS.