HPE5 ZIC2
Supported
Disease ID
HPE5
Gene ID
ZIC2
Updated
Oct 7, 2025
v2.11.0
Clinical Links
GARD
6665
GeneReviews
NBK51932
MalaCard
HLP028
MedGen
355304
Mondo
0012322
OMIM
609637
Orphanet
2162
DECIPHER
ZIC2
Bioinformatical Links
gnomAD
ZIC2
STRipy
ZIC2
TR-Atlas
TR127312
WebSTR hg38
5374719
WebSTR hg19
STR_395661
TR Explorer
chr13:99985449-99985494
Suggest Edit

Disease
Name
Holoprosencephaly-5
Inheritance
Autosomal dominant
Description
Holoprosencephaly associated with mutations in the ZIC2 gene1 .
Prevalence
1.4 1,000,000
0.05-0.23/100,000; math done by 40% of pathogenic variants in ZIC2 are expansion2 ; 5% of non-syndromic HPE are ZIC2 gene2 , and nonsyndromic HPE is 25-50% of HPE, which affects 1/10,000 newborns3 - ZIC2 is 9.2% of HPE cases, which occur in 1/16,000 live births4 . Holoprosencephaly has worldwide distribution5 , but STR-specific distribution is unknown.
Age of Onset(Typical)Years0  00  0
Age of Onset Details
0

Locus
hg19
chr13:100637702-100637748
hg38
chr13:99985448-99985494
t2t
chr13:99196358-99196404
Details
The benign allele of 15 repeats expands to 25 repeats to cause disease6 , although the expansion can potentially present with a mild phenotype7
Mechanism
LoF
Polyalanine expansion interfering with DNA binding and transcriptional activation8,9 .
Year
200110
Location in Gene
Coding Exon 3
Gene Strand

Alleles
Ref. Motif
GCN
Pathogenic (ref.)
GCN
Pathogenic (gene)
CNG
BenignPathogenicUnits15  1525  25

gnomAD

Pathogenic genotype frequency data is not displayed for this locus because a substantial number of large alleles failed manual review by the gnomAD team.

References

Direct supporting references for info on this page.

1
Ontology Lookup Service (OLS)
mondo:0012322
2
genereviews:NBK1530
3
Nonsyndromic holoprosencephaly: MedlinePlus Genetics
url:medlineplus.gov/genetics/condition/nonsyndromic-holoprosencephaly/
4
Holoprosencephaly.
Christèle,Dubourg, Claude,Bendavid, Laurent,Pasquier, Catherine,Henry, Sylvie,Odent, Véronique,David
Orphanet journal of rare diseases · 2007-02-02
pmid:17274816
5
Orphanet: Holoprosencephaly
orphanet:2162
6
POLYALANINE TRACT DISORDERS AND NEUROCOGNITIVE PHENOTYPES
Cheryl,Shoubridge, Jozef,Gecz
Madame Curie Bioscience Database [Internet] · 2013-01-01
genereviews:NBK51932
7
P703: Pathogenic ZIC2 polyalanine expansion detected by exome sequencing in a family with multi-generation holoprosencephaly
Nichole,Owen, Liesbeth,Vossaert, Lorraine,Potocki, Elizabeth,Mizerik
Genetics in Medicine Open · 2024-01-01
doi:10.1016/j.gimo.2024.101607
8
The full spectrum of holoprosencephaly-associated mutations within the ZIC2 gene in humans predicts loss-of-function as the predominant disease mechanism.
Erich,Roessler, Felicitas,Lacbawan, Christèle,Dubourg, Aimee,Paulussen, Jos,Herbergs, Ute,Hehr, Claude,Bendavid, Nan,Zhou, Maia,Ouspenskaia, Sherri,Bale, Sylvie,Odent, Vèronique,David, Maximilian,Muenke
Human mutation · 2009-04-01
pmid:19177455
9
In vitro analysis of partial loss-of-function ZIC2 mutations in holoprosencephaly: alanine tract expansion modulates DNA binding and transactivation.
Lucia,Brown, Melinda,Paraso, Ruth,Arkell, Stephen,Brown
Human molecular genetics · 2004-12-08
pmid:15590697
10
Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination.
L Y,Brown, S,Odent, V,David, M,Blayau, C,Dubourg, C,Apacik, M A,Delgado, B D,Hall, J F,Reynolds, A,Sommer, D,Wieczorek, S A,Brown, M,Muenke
Human molecular genetics · 2001-04-01
pmid:11285244

Additional Literature

Additional literature related to this locus.

Raw PubMed search results
(All PubMed results returned by searching for this gene, tandem repeats, and disease, in medline format)

Identification of a novel non-coding deletion in Allan-Herndon-Dudley syndrome by long-read HiFi genome sequencing.
Jihoon G,Yoon, Seungbok,Lee, Soojin,Park, Se Song,Jang, Jaeso,Cho, Man Jin,Kim, Soo Yeon,Kim, Woo Joong,Kim, Jin Sook,Lee, Jong-Hee,Chae
BMC medical genomics · 2025-03-03
pmid:40033291