Non-syndromic familial congenital anorectal malformations

Gene: ZIC3

Green List (high evidence)

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Comment when marking as ready: Gene checked.

Created: 1 Nov 2018, 12:34 p.m.

Gene is on expert list from Dr Charles Shaw-Smith (Royal Devon and Exeter NHS Foundation Trust)

Created: 19 Sep 2018, 4:21 p.m.

Comment on publications: Added phenotypes from papers reported in Hilger et al.

Created: 6 Sep 2018, 3:53 p.m.

Comment on list classification: Rating this gene green as ZIC3 variants have been found in more than 3 families with VACTERL or VACTERL-like phenotypes that include anorectal malformations.

Created: 6 Sep 2018, 3:51 p.m.

Gene added to panel as found to be candidate gene by Hilger et al 2015 (PMID: 26294094) who performed targeted sequencing of 123 patients with VATER/VACTERL or VATER/VACTERL-like phenotype. All patients had anorectal malformations. They identified an identical, probably disease-causing ZIC3 missense mutation (p.Gly17Cys) in four patients from 3 families. 2 patients also had other mutations (in IFT57 and TTC21B). The amino acid change is in a highly conserved residue and predicted to be deleterious in 4 out of 5 prediction algorithms. In situ hybridization analyses in mouse embryos between E9.5 and E14.5 revealed Zic3 expression in limb and prevertebral structures. Hilger et al 2015 also report that ZIC3 deletion/variants were found in patients from 5 other families with VATER/VACTERL or VATER/VACTERL-like association without hydrocephalus but with anorectal malformations (Purandare et al., 1999, Ware et al., 2004 (PMID: 14681828), Wessels et al., 2010 (PMID: 20452998), Chung et al., 2011 (PMID: 21465648)). The gene is also on the Illumina panel for VACTERL Association, X-linked. ZIC3 is listed as associated with "VACTERL association, X-linked" in OMIM, and anal atresia is a phenotype for this disorder.

Created: 4 Aug 2018, 10:12 p.m.