FIG4 – Yunis-Varon Syndrome

Yunis-Varon syndrome (YVS) is a rare autosomal recessive disorder characterized by cleidocranial dysplasia, digital anomalies, and severe neurological impairment with vacuolation of the central nervous system, skeletal muscles, and cartilages. Initial genetic studies identified biallelic null FIG4 variants as the cause of YVS, implicating loss of phosphoinositide phosphatase activity in pathogenesis ([PMID:24088667]).

In a 2013 case report, whole-exome sequencing of a YVS patient revealed compound heterozygous FIG4 splice-site and frameshift mutations, c.1750+1del ([PMID:24088667]) and c.2285_2286del (p.Ser762fs) ([PMID:24088667]). A subsequent study described four affected individuals from three unrelated families harboring frameshift and nonsense variants, including c.463C>T (p.Gln155Ter) ([PMID:23623387]). Together, these reports establish an inheritance mode of autosomal recessive transmission with homozygous or compound heterozygous null alleles.

All probands exhibited profound skeletal dysplasia (e.g., cleidocranial anomalies) and global developmental delay, consistent across pedigrees segregating null FIG4 variants. Segregation analysis confirmed that unaffected carriers did not develop YVS, further supporting pathogenicity of biallelic FIG4 loss-of-function alleles.

Functional assays in Fig4-null mice recapitulated key human phenotypes, including neurodegeneration, vacuolation of neurons and osteoblasts, and reduced trabecular bone volume. Rescue experiments demonstrated that expression of wild-type FIG4—but not null or missense disease variants—corrected vacuolar defects in fibroblasts and osteoblasts, confirming loss of PI(3,5)P2 phosphatase activity as the disease mechanism ([PMID:23623387]).

FIG4 encodes a SAC1 domain phosphoinositide phosphatase essential for regulation of PI(3,5)P2 levels and endosomal–lysosomal trafficking. Loss of FIG4 activity impairs lysosomal fission, disrupts autophagy, and elevates intralysosomal Ca2+, linking molecular dysfunction to the YVS phenotype.

Collectively, genetic and experimental evidence support a Strong clinical validity for the FIG4–Yunis-Varon syndrome association. Additional AR probands and extended segregation would further solidify evidence. Key Take-home: Biallelic null FIG4 variants cause Yunis-Varon syndrome via disruption of PI(3,5)P2 homeostasis, enabling precise molecular diagnosis and informing potential lysosome-targeted therapies.

References

• Journal of human genetics • 2013 • Novel FIG4 mutations in Yunis-Varon syndrome. PMID:24088667
• American journal of human genetics • 2013 • Yunis-Varón syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase PMID:23623387

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