GZF1 – Larsen syndrome

Recent studies have established a strong association between biallelic truncating variants in GZF1 and a distinct form of Larsen syndrome characterized not only by skeletal abnormalities but also by severe myopia and retinal detachment (PMID:28475863; PMID:33009817).

In a multiplex consanguineous Saudi family, a homozygous truncating variant was identified, while an independent study in two Chinese patients uncovered compound heterozygous frameshift changes. These observations were based on detailed autozygome and exome analyses that provided clear segregation of the variants with the affected phenotype (PMID:28475863).

Genetic evidence is supported by the detection of multiple truncating variants, including the selected variant c.1216_1219dup (p.His407fs). Such variants were detected in independent families, reinforcing the autosomal recessive inheritance pattern and implicating a loss-of-function mechanism in disease causation (PMID:28475863).

A subsequent multi‑patient study further validated the association by identifying additional novel frameshift variants in GZF1 in affected individuals presenting with hip dislocation, scoliosis, severe myopia, and hearing loss. The functional impact was corroborated by cellular assays that demonstrated reduced transcript and protein levels, indicating a clear loss of function as the underlying pathomechanism (PMID:33009817).

Experimental assessments have shown that mutant GZF1 proteins are either absent or mislocalized in patient-derived cells. These functional studies, alongside transcriptional dysregulation profiles enriched for matrix protein genes, align with the severe ocular and articular phenotypes observed and support a critical developmental role for GZF1.

Integrating these genetic and experimental findings, the association between GZF1 variants and Larsen syndrome is robust, with consistent autosomal recessive inheritance and clear evidence of a loss‑of‑function mechanism. Key take‑home: The identification of biallelic truncating GZF1 variants provides a valuable diagnostic marker for tailoring patient management in Larsen syndrome.

References

• American journal of human genetics • 2017 • GZF1 Mutations Expand the Genetic Heterogeneity of Larsen Syndrome PMID:28475863
• Clinical genetics • 2021 • Novel GZF1 pathogenic variants identified in two Chinese patients with Larsen syndrome PMID:33009817

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