ZIC1 – Dandy-Walker Syndrome

Heterozygous loss of ZIC1 has been observed in three unrelated individuals across two studies presenting with Dandy-Walker malformation, including one female with an interstitial 3q23–q25.1 deletion encompassing ZIC1 and ZIC4 (PMID:21204220) and two of three patients carrying overlapping 3q deletions that include ZIC1 (PMID:23679990). Mouse models demonstrate that Zic1 haploinsufficiency leads to cerebellar hypoplasia and vermis defects (PMID:26340333), supporting a loss-of-function mechanism in humans. However, hemizygosity of ZIC1–ZIC4 is neither necessary nor sufficient for Dandy-Walker malformation, as 11 additional DWM patients lacked 3q deletions (PMID:23679990). No segregation data are reported. Taken together, current evidence is limited and suggests that ZIC1 haploinsufficiency may contribute to Dandy-Walker syndrome in a subset of patients, with variable penetrance likely influenced by additional loci.

Key take-home: Heterozygous ZIC1 deletions have limited evidence for causality in Dandy-Walker syndrome; testing may be considered when other etiologies are excluded.

References

• American journal of medical genetics. Part A • 2011 • Dandy-Walker malformation associated with heterozygous ZIC1 and ZIC4 deletion: Report of a new patient. PMID:21204220
• Orphanet journal of rare diseases • 2013 • Dandy-Walker malformation and Wisconsin syndrome: novel cases add further insight into the genotype-phenotype correlations of 3q23q25 deletions. PMID:23679990
• American journal of human genetics • 2015 • Gain-of-Function Mutations in ZIC1 Are Associated with Coronal Craniosynostosis and Learning Disability. PMID:26340333

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