Locus HPE5 ZIC2

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

HPO Terms

HP:0000028 Cryptorchidism HP:0000079 Abnormality of the urinary system HP:0000093 Proteinuria HP:0000161 Median cleft upper lip HP:0000202 Orofacial cleft HP:0000218 High palate HP:0000238 Hydrocephalus HP:0000243 Trigonocephaly HP:0000252 Microcephaly HP:0000256 Macrocephaly HP:0000286 Epicanthus HP:0000289 Broad philtrum HP:0000316 Hypertelorism HP:0000337 Broad forehead HP:0000340 Sloping forehead HP:0000341 Narrow forehead HP:0000348 High forehead HP:0000377 Abnormal pinna morphology HP:0000400 Macrotia HP:0000437 Depressed nasal tip HP:0000453 Choanal atresia HP:0000457 Depressed nasal ridge HP:0000458 Anosmia HP:0000463 Anteverted nares HP:0000470 Short neck HP:0000488 Retinopathy HP:0000490 Deeply set eye HP:0000508 Ptosis HP:0000520 Proptosis HP:0000528 Anophthalmia HP:0000567 Chorioretinal coloboma HP:0000568 Microphthalmia HP:0000574 Thick eyebrow HP:0000581 Blepharophimosis HP:0000582 Upslanted palpebral fissure HP:0000601 Hypotelorism HP:0000612 Iris coloboma HP:0000648 Optic atrophy HP:0000664 Synophrys HP:0000776 Congenital diaphragmatic hernia HP:0000819 Diabetes mellitus HP:0000830 Anterior hypopituitarism HP:0000863 Central diabetes insipidus HP:0000871 Panhypopituitarism HP:0000873 Diabetes insipidus HP:0000929 Abnormal skull morphology HP:0001156 Brachydactyly HP:0001161 Hand polydactyly HP:0001249 Intellectual disability HP:0001250 Seizure HP:0001252 Hypotonia HP:0001257 Spasticity HP:0001263 Global developmental delay HP:0001272 Cerebellar atrophy HP:0001305 Dandy-Walker malformation HP:0001324 Muscle weakness HP:0001332 Dystonia HP:0001347 Hyperreflexia HP:0001360 Holoprosencephaly HP:0001382 Joint hypermobility HP:0001531 Failure to thrive in infancy HP:0001539 Omphalocele HP:0001629 Ventricular septal defect HP:0001636 Tetralogy of Fallot HP:0001641 Abnormal pulmonary valve morphology HP:0001679 Abnormal aortic morphology HP:0001743 Abnormality of the spleen HP:0001883 Talipes HP:0001943 Hypoglycemia HP:0001999 Abnormal facial shape HP:0002002 Deep philtrum HP:0002007 Frontal bossing HP:0002019 Constipation HP:0002020 Gastroesophageal reflux HP:0002072 Chorea HP:0002084 Encephalocele HP:0002093 Respiratory insufficiency HP:0002119 Ventriculomegaly HP:0002269 Abnormality of neuronal migration HP:0002507 Semilobar holoprosencephaly HP:0002553 Highly arched eyebrow HP:0002650 Scoliosis HP:0002902 Hyponatremia HP:0003312 Abnormal vertebral body morphology HP:0004409 Hyposmia HP:0005280 Depressed nasal bridge HP:0005469 Flat occiput HP:0006315 Solitary median maxillary central incisor HP:0006703 Aplasia/Hypoplasia of the lungs HP:0006870 Lobar holoprosencephaly HP:0006956 Lateral ventricle dilatation HP:0006988 Alobar holoprosencephaly HP:0007360 Aplasia/Hypoplasia of the cerebellum HP:0007370 Aplasia/Hypoplasia of the corpus callosum HP:0008736 Hypoplasia of penis HP:0008872 Feeding difficulties in infancy HP:0009099 Median cleft palate HP:0009738 Abnormal antihelix morphology HP:0009794 Branchial anomaly HP:0009804 Tooth agenesis HP:0009914 Cyclopia HP:0009924 Aplasia/Hypoplasia involving the nose HP:0010301 Spinal dysraphism HP:0010302 Spinal cord tumor HP:0010669 Hypoplasia of the zygomatic bone HP:0011100 Intestinal atresia HP:0011675 Arrhythmia HP:0012385 Camptodactyly HP:0012639 Abnormal nervous system morphology HP:0025670 Syntelencephaly HP:0032549 Persistent asymmetrical tonic neck reflex HP:0100336 Bilateral cleft lip HP:0100543 Cognitive impairment HP:0100596 Absent nares HP:0100702 Arachnoid cyst

Association

Mendelian

Locus

hg19chr13:100637702-100637748

hg38chr13:99985448-99985494

t2tchr13:99196358-99196404

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 activation^8,9.

Detection

Year

2001¹⁰

Location in Gene

Coding Exon 3

Gene Strand

Alleles

Ref. Motif

GCN

Ranges

Benign (ref.)

–

Benign (gene)

–

Pathogenic (ref.)

GCN

Pathogen. (gene)

GCN

Unknown (ref.)

–

Unknown (gene)

–

Interruption (ref.)

–

Interrup. (gene)

–

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.

Ontology Lookup Service (OLS)

mondo:0012322

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Nonsyndromic holoprosencephaly: MedlinePlus Genetics

url:medlineplus.gov/genetics/condition/nonsyndromic-holoprosencephaly/

Holoprosencephaly.

Christèle,Dubourg, Claude,Bendavid, Laurent,Pasquier, Catherine,Henry, Sylvie,Odent, Véronique,David

Orphanet journal of rare diseases · 2007-02-02

pmid:17274816

Vérification de la connexion...

orphanet:2162

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genereviews:NBK51932

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

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

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

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