Hereditary neuropathy or pain disorder

Gene: FAT3

Green List (high evidence)

Comment on list classification: As reviewed by Alexander Rossor, there is sufficient evidence available (three unrelated cases and functional evidence) for the association of FAT3 with neuropathy. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 27 Jul 2026, 6:45 p.m. | Last Modified: 27 Jul 2026, 6:45 p.m.

Panel Version: 8.24

PMID:41937739 (2026) reported the identification of biallelic FAT3 variants in three unrelated patients from a cohort of 3315 unrelated patients of Japanese descent with Charcot-Marie-Tooth disease (CMT)/ inherited peripheral neuropathies (IPN). Two patients had homozygous variants (Patient 1: p.Pro2041His; Patient 2: p.Cys3776Tyr) and one had compound heterozygous variants (patient 3: p.Met1749Val/ p.Arg3276Gln).

All three 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.

This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 27 July 2026).

Created: 27 Jul 2026, 6:42 p.m. | Last Modified: 27 Jul 2026, 6:42 p.m.

Panel Version: 8.21

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
peripheral neuropathy, MONDO:0005244

Publications

• 41937739

Green List (high evidence)

3 unrelated individuals
Sources: Expert list

Created: 11 Apr 2026, 2:51 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
axonal sensory and motor peripheral neuropathy; cranial neuropathy; scoliosis; respiratory failure; pseudoobstruction

Publications

• PMID: 41937739