LITAF

Inheritance Pattern: AD

Disease ID:MONDO:0010995

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0015626

Submitter: ClinGen

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. **Recuration Update**: One additional publication was curated, providing new genetic evidence supporting the association between LITAF and autosomal dominant Charcot-Marie-Tooth disease type 1C. Peddareddygari et al. (2023; PMID: 37868241) reported a 62-year-old woman with a mild demyelinating peripheral neuropathy who carried the heterozygous LITAF c.479G>A (p.Arg160His) variant. The patient initially received a diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) because extensive evaluation for acquired causes was unrevealing, but lack of response to immunotherapy prompted genetic testing, which identified the LITAF variant. The affected residue is highly conserved, and a different pathogenic substitution at the same amino acid (p.Arg160Cys) has previously been reported in individuals with LITAF-associated Charcot-Marie-Tooth disease, supporting the functional importance of this residue. The study also included in silico analyses and protein structural modeling predicting that the p.Arg160His substitution disrupts LITAF protein structure. However, no segregation analysis, parental testing, confirmed de novo occurrence, or variant-specific functional studies were performed. Based on the compatible phenotype and available genetic evidence, this proband was scored as 0.5 point for genetic evidence.

Inheritance Pattern: AD

Disease ID:MONDO:0010995

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0010995

Submitter: Labcorp Genetics (formerly Invitae)