3q24 Region (includes ZIC1)

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.

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)).

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)).

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)).

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.