Submission Details

LITAF/SIMPLE was first reported in relation to autosomal dominant Charcot-Marie-Tooth Disease in 2003 (Street et al., 2003; PMID: 12525712). The phenotypes associated with LITAF/SIMPLE variants include distal muscle weakness, pes cavus, decreased motor and sensory nerve conduction velocities, and impaired vibration or pain sensation in the lower limbs. At least 15 unique missense variants have been reported in humans, with few other types of mutations reported. Evidence supporting this gene-disease relationship includes case-level data, segregation and experimental data. Variants in this gene have been reported in over 25 probands in 6 different publications, although no confirmed de novo or null variants have been observed in the literature (PMIDs: 24880540, 19541485, 28211240, 16787513, 15776429, 12525712). Variants in this gene also segregated with disease in over 50 additional family members across seven different families. This gene-disease relationship is supported by expression studies, functional studies, and an animal model. LITAF/SIMPLE was once predicted to have a role in protein degradation pathways, however recent research has shown that it is instead a zinc-binding membrane protein that embeds itself with an anchor located within the LITAF domain where most of the pathogenic mutations cluster (PMID: 27927196). Additionally, LITAF/SIMPLE is present in both developing and adult rat/mouse schwann cells and not in the axons supporting a demyelinating neuropathy phenotype (PMID:12525712). In summary, LITAF/SIMPLE is MODERATELY associated with autosomal dominant Charcot-Marie-Tooth Disease. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Charcot Marie Tooth Gene Curation Expert Panel on Apr 7, 2020.