ZNF517 – Zimmermann-Laband Syndrome

The association between ZNF517 (HGNC:27984) and Zimmermann-Laband Syndrome (MONDO_0000200) has been proposed in the context of a study investigating overlapping features of Temple-Baraitser and Zimmermann-Laband syndromes. The report, based on whole genome sequencing of a proband, identified mutations in three genes, with a single missense variant in ZNF517 drawing attention as a potential contributor to the phenotype (PMID:27282200). This observation underscores the complexity of genetic modifiers in syndromic conditions and suggests that ZNF517 may be among several candidate genes influencing the clinical spectrum.

Genetic evidence for ZNF517 in this syndrome is currently limited, as only one ZNF517 variant has been reported. In the case described, the variant c.726A>T (p.Lys242Asn) was identified in a proband with features overlapping Zimmermann-Laband Syndrome, but no additional affected relatives or segregation data were documented (PMID:27282200). This single observation places the gene-disease association in the Limited category according to ClinGen criteria.

The reported missense variant, c.726A>T (p.Lys242Asn), is the sole variant considered for ZNF517 in the context of this association. As there are no recurrent or founder mutations reported for ZNF517 in this disorder, the genetic evidence remains sparse. The lack of further segregation studies limits the overall strength of the assertion that ZNF517 plays a direct causative role in Zimmermann-Laband Syndrome.

Although Zimmermann-Laband Syndrome is typically inherited in an autosomal dominant manner, the current data for ZNF517 do not provide robust familial or case series evidence. This paucity of supportive genetic data means that while the variant is intriguing, it does not yet meet a threshold for stronger clinical validity. Additional cases and extended family analyses are needed to bolster the genetic evidence.

Functional studies in the cited work largely focused on other candidate genes, and no gene-specific assays have been performed for ZNF517. Without experimental data such as cellular assays, animal models, or rescue experiments specific to ZNF517, the functional evidence remains limited. Future research aimed at assessing the impact of the c.726A>T (p.Lys242Asn) variant on protein function and downstream pathways is warranted.

In summary, while preliminary genetic findings suggest that ZNF517 may be associated with Zimmermann-Laband Syndrome, the evidence remains limited by the presence of a single reported variant without additional segregation or functional corroboration. Clinicians and researchers should interpret these findings cautiously, and comprehensive genetic testing remains critical to elucidate the full molecular etiology of the syndrome.

References

• BMC Medical Genetics • 2016 • Temple-Baraitser Syndrome and Zimmermann-Laband Syndrome: one clinical entity? PMID:27282200

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