ZIC2 – Holoprosencephaly

ZIC2, located at chromosome 13q32, encodes a C2H2‐type zinc‐finger transcription factor essential for forebrain patterning. Heterozygous loss‐of‐function variants in ZIC2 underlie a non‐syndromic form of holoprosencephaly (HPE), a spectrum of failed or incomplete separation of the prosencephalon into two cerebral hemispheres (PMID:19955556).

Genetic studies have identified ZIC2 mutations in 157 affected individuals from 119 unrelated kindreds, of which ~70% are de novo events. Variants span nonsense, frameshift, missense, splice and polyalanine‐tract expansions, consistent with haploinsufficiency. A prototypical missense change, c.1069C>G (p.His357Asp), was reported de novo in a Han infant with semilobar HPE and arachnoid cyst (PMID:30855487).

Autosomal dominant inheritance with incomplete penetrance is supported by familial recurrence in >10 kindreds and documented parental mosaicism. De novo cases account for most probands, and segregation studies confirm pathogenicity in multiple families (8 affected relatives) with consistent midline brain defects (PMID:19955556).

Functional evidence establishes ZIC2 haploinsufficiency as the mechanism of disease. Mouse Zic2 mutants manifest forebrain midline defects preceding Shh pathway activation, indicating an organizer‐region defect in gastrulation (PMID:18617531). In vitro assays show that alanine‐tract expansions and missense changes impair DNA binding and transcriptional activity (PMID:15590697). The mutation spectrum predicts loss‐of‐function as the predominant disease mechanism (PMID:19177455).

No robust conflicting evidence has been reported. Comprehensive cohort studies consistently identify ZIC2 variants in HPE patients, and no common benign polymorphisms account for the observed phenotypes.

Integration of genetic and experimental data yields a definitive gene–disease relationship. ZIC2 mutation analysis is recommended in the molecular evaluation of HPE, informing prognosis, recurrence risk, and early prenatal diagnosis. Key Take‐home: ZIC2 haploinsufficiency is a definitive cause of autosomal dominant holoprosencephaly, with broad utility in clinical diagnostics.

References

• Journal of medical genetics • 2010 • Mutations in ZIC2 in human holoprosencephaly: description of a novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals. PMID:19955556
• Human mutation • 2009 • The full spectrum of holoprosencephaly-associated mutations within the ZIC2 gene in humans predicts loss-of-function as the predominant disease mechanism. PMID:19177455
• Human molecular genetics • 2008 • Zic2-associated holoprosencephaly is caused by a transient defect in the organizer region during gastrulation. PMID:18617531
• Human molecular genetics • 2005 • In vitro analysis of partial loss-of-function ZIC2 mutations in holoprosencephaly: alanine tract expansion modulates DNA binding and transactivation. PMID:15590697
• Medicine • 2019 • Case report: a novel mutation in ZIC2 in an infant with microcephaly, holoprosencephaly, and arachnoid cyst. PMID:30855487

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