Biallelic variants in FAT3 cause axonal neuropathy with multisystem neurodevelopmental features

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Inherited peripheral neuropathies often lack a genetic explanation.
• Advances in diagnostics are crucial for understanding rare genetic disorders.

Purpose of the Study:

• To investigate the role of biallelic variants in the FAT3 gene in inherited axonal neuropathies.
• To identify novel genetic causes for unexplained peripheral neuropathies.

Main Methods:

• Identified biallelic FAT3 variants in three unrelated patients with inherited peripheral neuropathies.
• Performed segregation analysis, in silico modeling, and functional studies in Drosophila and mouse models.
• Evaluated clinical phenotypes including muscle weakness, cranial nerve involvement, and systemic abnormalities.

Main Results:

• Patients presented with progressive distal muscle weakness, cranial nerve deficits, and respiratory muscle paralysis.
• One patient exhibited central hypomyelination, autonomic dysfunction, and developmental anomalies.
• FAT3 variants were ultra-rare, affected conserved residues, segregated with disease, and impaired protein function in model organisms.

Conclusions:

• FAT3 is identified as a novel gene responsible for autosomal recessive axonal neuropathies.
• Findings suggest a FAT3-related multisystem neurodevelopmental disorder involving motor neuron degeneration and systemic abnormalities.