Renal ciliopathies
Gene: ZNF423
After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains Amber. Chaki paper from 2012 has not been well-replicated in the decade since. Some individual reports but nothing convincing. Lack of clear biallelic LOF variants reported in humans.Created: 30 Jan 2023, 3:08 p.m. | Last Modified: 30 Jan 2023, 3:08 p.m.
Panel Version: 2.3
Changed tags to Q3_22_rating and Q3_22_expert_review so that this gene will go in the next report (Oct 2022)Created: 5 Oct 2022, 4:35 p.m. | Last Modified: 5 Oct 2022, 4:35 p.m.
Panel Version: 1.64
There are now two unrelated families with homozygous variants and two cases with heterozygous variants in this gene associated with nephronophthisis or Joubert syndrome. Zfp423-mutant mice harbouring some variants (but not all - including one patient variant) displayed neuroanatomical abnormalities that were consistent with the human phenotype. Overall the evidence is borderline and therefore this gene will be flagged for GMS expert review to determine whether it should be upgraded to green at this stage.Created: 31 Mar 2022, 1:39 p.m. | Last Modified: 31 Mar 2022, 1:39 p.m.
Panel Version: 1.61
Chaki et al., 2012 (PMID: 22863007) identified a homozygous 2738C-T variant in the ZNF423 gene (p.P913L) in two Turkish siblings with with nephronophthisis-14 manifested as infantile-onset kidney disease, cerebellar vermis hypoplasia, and situs inversus. Heterozygous variants (p.P506fsX43 and p.H1277Y, respectively) were found in two additional unrelated patients with Joubert syndrome.
Deshpande et al. 2020 (PMID: 32925911) later produced Zfp423-mutant mice harbouring various variants, including the p.P913L and p.P506fsX43 patient variants. Notably, p.P913L did not result in any abnormalities in brain structures or gait, while mice homozygous for p.H1277Y displayed features such as gross ataxia, vermis agenesis, reduced cortical thickness, and incomplete corpus callosum.
Tang et al., 2022 (PMID: 33323469) identified a Chinese patient with a homozygous p.H353Q variant in the ZNF423 gene for which both parents were heterozygous carriers. The phenotype was consistent with Joubert syndrome including nephronophthisis, developmental delay and cerebellar vermis hypoplasia.Created: 29 Mar 2022, 3:57 p.m. | Last Modified: 29 Mar 2022, 3:57 p.m.
Panel Version: 1.61
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Joubert syndrome 19, OMIM:614844; Nephronophthisis 14, OMIM:614844
Publications
Comment when marking as ready: Homozygous mutations only reported in two siblings with nephronophthisis and two Joubert patients found to have heterozygous mutationsCreated: 23 Jan 2017, 12:15 p.m.
On current diagnostic panel; no positive families in patient cohort to date.Created: 16 Mar 2016, 4:02 p.m.
Phenotypes
Joubert syndrome; nephronphthisis
Publications
Variants in this GENE are reported as part of current diagnostic practice
Tag Q3_22_rating was removed from gene: ZNF423. Tag Q3_22_expert_review was removed from gene: ZNF423.
Tag Q1_22_expert_review was removed from gene: ZNF423. Tag Q3_22_rating tag was added to gene: ZNF423. Tag Q3_22_expert_review tag was added to gene: ZNF423.
Phenotypes for gene: ZNF423 were changed from Nephronophthisis 14; Joubert syndrome 19, 614844; Joubert syndrome with oculorenal defect; Joubert syndrome 19; Nephronophthisis 14, 614844 to Joubert syndrome 19, OMIM:614844; Nephronophthisis 14, OMIM:614844
Publications for gene: ZNF423 were set to 22863007
Tag Q1_22_expert_review tag was added to gene: ZNF423.
gene: ZNF423 was added gene: ZNF423 was added to Renal ciliopathies. Sources: Emory Genetics Laboratory,Other,Expert list,Expert Review Amber,Radboud University Medical Center, Nijmegen,Orphanet Mode of inheritance for gene: ZNF423 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: ZNF423 were set to 22863007 Phenotypes for gene: ZNF423 were set to Nephronophthisis 14; Joubert syndrome 19, 614844; Joubert syndrome with oculorenal defect; Joubert syndrome 19; Nephronophthisis 14, 614844