ZMAT2 – Congenital Radioulnar Synostosis

Congenital radioulnar synostosis (RUS) is a rare skeletal disorder characterized by fusion of the radius and ulna (PMID:32247068). The etiology of RUS remains largely unknown, and there are limited treatment options. ZMAT2 encodes a zinc finger matrin-type protein implicated in RNA processing, but its role in skeletal development has not been previously described.

Genetic evidence for ZMAT2 in RUS is limited to a single de novo missense variant identified by whole-exome sequencing in a 5-year-old boy with unilateral radioulnar fusion (PMID:32247068). No additional familial cases or segregation data have been reported.

The inheritance pattern is consistent with an autosomal dominant de novo mechanism. No affected relatives with segregating variants have been documented.

Functional assays in zebrafish support pathogenicity: zmat2 knockdown produced pectoral fin hypoplasia and dorso-ventral patterning defects consistent with reduced BMP signaling. Partial rescue was achieved by zbmp2b RNA overexpression, full rescue by wild-type zzmat2, and failure to rescue by the patient-derived mutant zzmat2 (PMID:32247068).

These data indicate that ZMAT2 loss of function disrupts BMP-mediated limb development, providing biological plausibility for its role in RUS.

Key take-home: While evidence is currently limited to a single case with strong functional concordance, ZMAT2 represents a candidate gene for RUS and warrants inclusion in diagnostic gene panels.

References

• Bone • 2020 • ZMAT2, a newly-identified potential disease-causing gene in congenital radioulnar synostosis, modulates BMP signaling. PMID:32247068

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