Submission Details

FIG4 was first reported in relation to autosomal recessive Charcot-Marie-Tooth disease (CMT) in 2007 (Chow et al., PMID: 17572665). This publication reported a spontaneous mouse mutant, the 'pale tremor' mouse, that displayed a recessive inherited disorder similar to Charcot-Marie-Tooth disease. Both the mice and humans with variants in FIG4 displayed tremors, gait abnormalities, neuronal and axonal degeneration, and decreased NCV. This gene was also asserted in relation to Yunis-Varón syndrome in 2013 (Campeau et al., PMID: 23623387), however a review of the phenotypes, molecular mechanism, and published assertions demonstrated that the disorders should be considered part of the same spectrum and thus assessed together. Over 100 variants (e.g. missense, nonsense, frameshift, etc.) have been reported in humans since these initial reports. The most frequent variant is the hypomorphic c.122T>C (p.Ile41Thr) founder variant, most commonly observed in individuals with a less-severe phenotype limited to the peripheral nervous system (Lenk et al. 2011, PMID: 21655088). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in many probands, with three distinct publications being evaluated in this curation (PMIDs: 17572665, 23623387, 29468183). No strongly supportive segregation evidence was characterized among these publications. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is biallelic loss of function, with the more-severe Yunis-Varón probands usually having two functionally null variants and the less-severe CMT probands usually having a null variant in-trans with a hypomorphic variant, retaining some small amount of function. This gene-disease association is supported by several pieces of experimental evidence. FIG4 forms a complex with PIKfyve and arPIKfyve in mammalian cells to regulate the production of PI(3,5)P2, a coating for intracellular organelle membranes that helps regulate their membrane trafficking. Disruption of this complex also decreases levels of PI(3,5)P2, causing enlarged vacuoles, increased cell death, and the phenotypes of a neuropathy (Guo et al. 2012, PMID: 22157617). RT-PCR of mouse fetal and adult RNA in neurons confirmed that FIG4 was abundantly expressed in both the central and peripheral nervous system during development, and maintained a high level in sciatic nerves even into adulthood. The aforementioned 'pale tremor' mice served as a high quality model that recapitulated many of the phenotypes observed in both CMT and Yunis-Varón with the same loss-of-function mechanism. Furthermore, experimental efforts with an AAV9 viral vector were able to express WT human FIG4 in the 'pale tremor' mice and show rescuing of the severe disease phenotypes displayed (Presa et al. 2021, PMID: 33878035). In summary, FIG4 is definitively associated with autosomal recessive Charcot-Marie-Tooth disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Prenatal Secondary:

The existing literature supports prenatal descriptions in patients with a clinical diagnosis of Yunis-Varon syndrome, including hydrops fetalis, polyhydramnios, brain abnormalities, microcephaly and prematurity (PMID: 18203163, 23623387). Furthermore, craniofacial abnormalities, chest and skeletal dysplasia (including limb abnormalities), congenital heart defects, and genitourinary anomalies that characterize Yunis-Varon syndrome can potentially be identified through prenatal imaging. However, few of these cases had molecular testing and as such, there is insufficient evidence linking homozygous and compound heterozygous variants in FIG4-associated Yunis-Varon syndrome with prenatal presentation (PMID: 32385905, 31087399). Currently, there is no confirmed molecular association between FIG4-associated Yunis-Varon syndrome and pregnancy loss or infertility.