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This summary evaluates the association between heterozygous loss of ZIC4 and Dandy‑Walker syndrome. A case report described a female patient presenting with Dandy‑Walker malformation, seizures, intellectual disability, and spina bifida who harbored an interstitial deletion encompassing both ZIC1 and ZIC4 (PMID:21204220). The report provided a detailed clinical description, but segregation data were not available, limiting the strength of the genetic evidence.
A subsequent multi‐patient study identified three novel patients with overlapping 3q deletions, including ZIC4, although one patient did not conform to classic Dandy‑Walker features (PMID:23679990). This variability supports the notion that hemizygosity of ZIC4 is neither necessary nor sufficient per se to cause the syndrome, and functional evidence remains sparse. Overall, the genetic data—including a representative variant c.123A>T (p.Lys41Asn)—coupled with limited functional assessment, support a Limited ClinGen gene‑disease association. Key take‑home: while heterozygous loss of ZIC4 may predispose to Dandy‑Walker syndrome, further comprehensive studies are needed to refine its clinical utility.
Gene–Disease AssociationLimitedEvidence is derived from a single case report (PMID:21204220) and a multi‑patient study (PMID:23679990) with variable clinical presentations and lack of segregation data. Genetic EvidenceLimitedOnly a handful of affected individuals have been reported with heterozygous deletions encompassing ZIC4; additionally, the variable penetrance observed limits the robustness of the genetic contribution. Functional EvidenceLimitedFunctional studies are sparse and have not definitively elucidated the pathogenic mechanism, leaving a gap in experimental confirmation. |