Biallelic variants in FAT3 cause axonal neuropathy with multisystem neurodevelopmental features.

PURPOSE: Despite advances in diagnostics, many inherited peripheral neuropathies remain genetically unexplained. We investigated whether biallelic variants in FAT3 (FAT Atypical Cadherin 3) are implicated in inherited axonal neuropathies.

METHODS

We identified biallelic FAT3 variants in three unrelated individuals among 3315 Japanese patients with inherited peripheral neuropathies. Variants were evaluated by segregation analysis, in silico modeling, and functional studies in Drosophila and mouse models.

RESULTS

All patients exhibited progressive distal muscle weakness and cranial nerve involvement, including tongue atrophy, dysarthria, and facial weakness. Two required ventilatory support because of respiratory muscle paralysis. One patient additionally showed central hypomyelination, autonomic dysfunction, and developmental anomalies, such as congenital scoliosis and intestinal pseudo-obstruction. Identified variants were ultrarare, affected conserved residues, segregated with disease, and were predicted to impair domain stability. FAT3 knockdown in Drosophila resulted in rough eye phenotype, shortened lifespan, impaired motor function, and defective motor neuron branching. Fat3 knockout and knockin mice displayed perinatal lethality, sciatic nerve axonal degeneration, and central nervous system abnormalities despite preserved motor performance.

CONCLUSION

Our findings establish FAT3 as a novel gene for autosomal-recessive axonal neuropathies and support the concept of a FAT3-related multisystem neurodevelopmental disorder characterized by motor neuron degeneration and systemic abnormalities.