ClinGen Dosage Sensitivity Curation Page

3q24 Region (includes ZIC1)

  • Curation Status: Complete
  • id: ISCA-46553
  • Date last evaluated: 2021-07-19
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 0


Location Information

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Evidence for haploinsufficiency phenotype
PubMed ID Description
15338008 Grinberg et al. (2004) identified seven individuals with Dandy-Walker malformation (DWM) who harbored large (>5Mb) de novo heterozygous deletions of the 3q2 region that encompassed ZIC1 (3q24) and its closely linked homolog ZIC4 (3q24) and many other genes. All deletions were non-recurrent. The seven individuals had DWM with hypoplasia and upward rotation of the cerebellar vermis and posterior fossa cyst. Three individuals had hydrocephaly, and all seven had cognitive deficits. Three individuals with deletions that extended to 3q22.2 had facial changes of the blepharophimosis-ptosis-epicanthus inversus syndrome likely due to deletion of FOXL2. The authors defined a 7Mb critical region for the Dandy-Walker malformation phenotype that encompassed ZIC1 and ZIC4. An eighth patient with a interstitial deletion of 3q24-q24.33 also had Dandy-Walker malformation, although this deletion did not encompass ZIC1 or ZIC4. The proximal breakpoint of their deletion was refined to a region approximately 250kb distal to ZIC1 and ZIC4, and semiquantitative RT-PCR analysis of lymphoblast mRNA demonstrated altered expression of both genes. To model the 3q deletions, the authors generated double heterozygous knockout mice (Zic1 +/- Zic4 +/-) that demonstrated a similar phenotype to individuals with 3q deletion. 85% of the double heterozygous knockout mice had a mild cerebellar phenotype, and 15% were severely affected, with marked foliar defects and disproportionate hypoplasia of the vermis, mimicking the cerebellar morphology of individuals with 3q deletion. Zic4 heterozygous knockout mice (Zic4+/-) had a distinct cerebellar phenotype of posterior cerebellar hypoplasia with mild anterior foliation defect. Zic1 heterozygous knockout mice (Zic1+/-) were grossly normal, but had disruptions of anterior folia.
21204220 Tohyama et al. (2011) reported a female patient with DWM who harbored a 14Mb de novo deletion of 3q23-q25.1 that encompassed ZIC1 and ZIC4 (chr3:142,479,100-156,504,521 [NCBI37/hg19]). The deletion was found by chromosomal microarray analysis and encompassed many other genes. Karyotyping of subject's lymphocytes confirmed a 46,XX,del(3)(q23q25.1) karyotype. The subject had severe developmental delay, bilateral hip dislocation, dysmorphic facial features, mild scoliosis, and developed generalized epilepsy at age 11 (additional features in Tohyama et al. (2011)).
21471554 Lim et al. (2011) report a male subject with a de novo 15Mb deletion of 3q22.3q-q25.2 that encompassed ZIC1, ZIC4, FOXL1, ATR and multiple additional genes (published: chr3:139,328,000-154,254,416 [NCBI36/hg18], remapped: chr3:137845310-152771726 [NCBI37/hg19]). The subject had Dandy-Walker malformation, blepharophimosis-ptosis-epicanthus inversus syndrome, and developmental delay (additional features in Lim et al. (2011)).
28503614 Ramineni et al. (2016) report a female patient with a 12Mb de novo deletion of 3q22.3-q24 that encompassed ZIC1, ZIC4, FOXL2 and multiple additional genes (chr3:136,403,035-148,341,113 [NCBI37/hg19]). The subject had features suggestive of a mild variant of Dandy-Walker malformation with hypoplasia of the cerebellar vermis with associated enlargement of the fourth cerebral ventricle, thinning of the corpus callosum, and blepharophimosis?ptosis?epicanthus inversus syndrome (additional details in Ramineni et al. (2016)).
22067867 Ramieri et al. (2011) report a five moth old male patient with Dandy-walker malformation, characterized by cerebellum vermis hypoplasia, in addition to microcephaly, microphthalmia, bilateral inguinal hernia, blepharophimosis?ptosis?epicanthus inversus syndrome and additional congenital anomalies. The subject harbored a deletion of 3q22.1-q25.2 identified by FISH.

Haploinsufficiency phenotype comments:

Deletion of the 3q24 region, including ZIC1, have been reported in individuals with intellectual disability, Dandy-Walker malformation, blepharophimosis, ptosis, and epicanthus inversus syndrome, and other features. The coordinates for this region were defined using the smallest deletion detected by array to date in Ramineni et al. (2016), PMID: 28503614; larger deletions involving this region have also been reported. Grinberg et al. (2004), PMID: 15338008 reported seven individuals with Dandy-Walker malformation (DWM) and additional neurodevelopmental phenotypes who had heterozygous de novo deletions that encompassed ZIC1 and its closely linked homolog ZIC4 (3q24) in addition to multiple other genes. The reported deletions were large (>5 Mb) and encompassed multiple cytobands on the q arm of chromosome 3. The authors defined an 7Mb critical region for the DWM phenotype that encompassed both ZIC1 and ZIC4 based on the smallest region of deletion overlap. Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) was present in several individuals with deletions that extended proximally to encompass FOXL2 (3q22.3). Since the initial report by Grinberg et al. (2004), additional large, non-recurrent 3q deletions that encompass both ZIC1 and ZIC4 have been reported in patients with DWM (see PMIDs above). While Ferraris et al. (2013), PMID: 23679990 report a novel patient and comment on three previously published cases with deletions of ZIC1 and ZIC4 without DWM, it is unclear whether these cases represent incomplete penetrance for the DWM phenotype due to uncertainty around the deletion breakpoints and uncertainty as to whether MRI was performed (PMIDs: 23679990, 16179233, 20215058, 23313878). Even though ZIC1 is believed to be the causative gene, there have been no reports of single gene deletions involving only ZIC1. For discussion of haploinsufficiency of the the gene ZIC1, please see the linked region (ISCA-37134).

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Whole gene duplications of the 3q24 region have not been previously reported. Therefore, the triplosensitivity score is 0.