Related Experiment Video
Updated: Jan 29, 2026
Following the Dynamics of Structural Variants in Experimentally Evolved Populations
Published on: February 3, 2023
Cerebral hypomyelination associated with biallelic variants of FIG4
Guy M Lenk1, Ian R Berry2, Chloe A Stutterd3,4,5
1Department of Human Genetics, University of Michigan, Ann Arbor, Michigan.
Abstract:
The lipid phosphatase gene FIG4 is responsible for Yunis-Varón syndrome and Charcot-Marie-Tooth disease Type 4J, a peripheral neuropathy. We now describe four families with FIG4 variants and prominent abnormalities of central nervous system (CNS) white matter (leukoencephalopathy), with onset in early childhood, ranging from severe hypomyelination to mild undermyelination, in addition to peripheral neuropathy. Affected individuals inherited biallelic FIG4 variants from heterozygous parents. Cultured fibroblasts exhibit enlarged vacuoles characteristic of FIG4 dysfunction. Two unrelated families segregate the same G > A variant in the +1 position of intron 21 in the homozygous state in one family and compound heterozygous in the other. This mutation in the splice donor site of exon 21 results in read-through from exon 20 into intron 20 and truncation of the final 115 C-terminal amino acids of FIG4, with retention of partial function. The observed CNS white matter disorder in these families is consistent with the myelination defects in the FIG4 null mouse and the known role of FIG4 in oligodendrocyte maturation. The families described here the expanded clinical spectrum of FIG4 deficiency to include leukoencephalopathy.
Insights
FIG4 gene variants cause peripheral neuropathy and central nervous system leukoencephalopathy in children. This study expands the clinical spectrum of FIG4 deficiency, revealing new insights into myelination defects.
Area of Science:
- Genetics
- Neurology
- Cell Biology
Background:
- The lipid phosphatase gene FIG4 is linked to Yunis-Varón syndrome and Charcot-Marie-Tooth disease Type 4J, a peripheral neuropathy.
- FIG4 dysfunction is characterized by enlarged vacuoles in cultured fibroblasts.
Purpose of the Study:
- To describe four families with FIG4 variants presenting with central nervous system (CNS) white matter abnormalities (leukoencephalopathy) and peripheral neuropathy.
- To investigate the clinical spectrum and genetic basis of FIG4 deficiency.
Main Methods:
- Clinical evaluation of four families with biallelic FIG4 variants.
- Analysis of fibroblast cultures to observe cellular phenotypes.
- Genetic sequencing to identify and characterize FIG4 variants, including splice site mutations.
Main Results:
- Four families presented with leukoencephalopathy and peripheral neuropathy, with onset in early childhood.
- A specific G>A splice donor site mutation in intron 21 was identified in two families, leading to a truncated FIG4 protein with partial function.
- Phenotypes ranged from severe hypomyelination to mild undermyelination, consistent with impaired oligodendrocyte maturation.
Conclusions:
- FIG4 deficiency presents an expanded clinical spectrum that includes leukoencephalopathy.
- The findings highlight the critical role of FIG4 in CNS white matter development and oligodendrocyte function.
- This research deepens the understanding of genetic leukoencephalopathies and peripheral neuropathies.
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