RSPO4 in anonychia congenita: Evidence of segregation without causation
Keywords:
Anonychia Congenita, RSPO4 gene, Consanguineous familyAbstract
Background: Anonychia congenita is a rare autosomal recessive disorder characterized by complete absence of fingernails and toenails, often without associated physical or mental abnormalities. RSPO4 gene mutations are a known genetic cause which plays a crucial role in the Wnt signaling pathway.
Methods: We examined a consanguineous family from Saudi Arabia with multiple individuals affected by nonsyndromic anonychia. Sanger confirmation identified a variant in exon 3 of RSPO4. Pedigree segregation analysis and electropherogram comparisons were performed.
Results: The homozygous missense variant c.317G>A (p.Arg106Gln) in RSPO4 was identified in all affected individuals. However, this variant is reported in ClinVar (VCV000784403.4) as likely benign and has a global allele frequency of approximately 2.1% in gnomAD. In silico pathogenicity predictions and population-scale genomic evidence argue against its role as a causative mutation.
Conclusion: Despite its segregation with the anonychia phenotype in the family, the c.317G>A variant in RSPO4 is unlikely to be pathogenic. This finding underscores the importance of integrating public genomic databases and in silico tools to avoid false-positive causal associations, especially in consanguineous pedigrees. Further analysis, including whole-genome sequencing and transcriptomic studies are required to identify the true pathogenic variants.
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