FIG4

Inheritance Pattern: AR

Disease ID:MONDO:0015626

Submitter: ClinGen

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.

Inheritance Pattern: Unknown

Disease ID:MONDO:0012945

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0008995

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0012640

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0012640

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0008995

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012640

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012945

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0012986

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012986

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0012640

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: AD

Disease ID:MONDO:0012945

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0015626

Submitter: Illumina

Inheritance Pattern: AD

Disease ID:MONDO:0012945

Submitter: ClinGen

*FIG4* was first reported in relation to autosomal dominant amyotrophic lateral sclerosis (ALS) type 11 in 2009 (Chow CY, et al., 2009, PMID: 19118816 ). ALS causes progressive degeneration of nerve cells in the spinal cord and brain. Dysfunctional endo-lysosomal and autophagic trafficking, leading to impaired proteostasis is common across ALS related genes. *FIG4*, also known as *SAC3*, is a phosphoinositide 5-phosphatase that regulates the cellular abundance of PI(3,5)P2, a signaling lipid located on the cytosolic surface of membranes of the late endosomal compartment. Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 16 rare variants have been reported in relation to ALS11. These variants have been reported in 16 probands across 8 publications (PMIDs: 19118816, 25299611, 25382069, 26742954, 27790088, 28051077, 35021275, and 29411640). Experimentally, this gene-disease relationship is supported by the role of *FIG4* in early endosome dynamics (PMID: 17556371 and 22157617) as well as model organisms with some overlapping features (PMID: 19793721 and 26708557). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. Of note, *FIG4* has also been reported in relation to Charcot-Marie-Tooth disease, type 4J (CMT4J), Yunis-Varon syndrome, and autosomal recessive polymicrogyria. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found ALS to be a distinct disease entity due to the autosomal dominant inheritance and differences in phenotype. It was curated separately from the additional disease entities. CMT4J and Yunis-Varon Syndrome, which are generally autosomal recessive, are on a single spectrum of severity with overlapping phenotypes and variants, and similar molecular mechanisms, therefore these entities were lumped together in a single curation performed by the Charcot-Marie-Tooth GCEP. Autosomal recessive polymicrogyria is an additional, distinct early onset seizure disorder, outside the scope of the ALS GCEP.

Inheritance Pattern: AR

Disease ID:MONDO:0008995

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0015626

Submitter: PanelApp Australia