Ehlers Danlos syndrome with a likely monogenic cause
Gene: ZNF469Comment on phenotypes: Previous phenotypes:
Brittle cornea syndrome 1, 229200;BCS;EDSVIB;Connective Tissue Disorders;Ehlers-Danlos syndrome type VIB;Brittle cornea syndromeCreated: 18 Mar 2021, 2:08 p.m. | Last Modified: 18 Mar 2021, 2:08 p.m.
Panel Version: 2.51
This gene was part of an initial gene list collated by Duncan Baker, Sheffield Diagnostic Genetics Service, January 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: ZNF469; Suggested initial gene rating: greenCreated: 3 Apr 2019, 3:41 p.m.
Comment on list classification: Changed status from Green to Amber due to a review from Dr Anthony Vandersteen, IWK Health centre in Halifax, Nova Scotia, Canada 'The brittle cornea syndrome is discussed in the new nosology and greatly overlaps with kyphoscoliotic EDS, so I would put PRDM5 and ZNF469 as green'.Created: 26 Apr 2017, 9:44 a.m.
In relation to the EDS pathogenetic scheme, ZNF469 belongs to 'Disorders of intracellular processes'. The scheme regroups EDS subtypes for which the proteins, coded by the causative genes, function within the same pathway, and which are likely to have shared pathogenic mechanisms, based on current knowledge.
Created: 18 Apr 2017, 12:03 p.m.
From Ehlers–Danlos Syndromes, Rare Types, Brady et al., 2017 (PMID:28306225):
Recently, a number of rare autosomal recessive entities with distinct molecular and biochemical abnormalities that clinically overlap with kEDS have been described; kEDS due to PLOD1 mutations, kEDS due to FKBP14 mutations, the Brittle cornea syndrome (BCS) (ZNF469 and PRDM5), the spondylodysplastic form of EDS caused by SLC39A13 mutations (previously called spondylocheirodysplastic EDS), and musculocontractural EDS (CHST14 and DSE)Created: 18 Apr 2017, noon
From The 2017 International Classification of the Ehlers–Danlos Syndromes. Malfait et al., 2017 (PMID:28306229): In relation to the EDS pathogenetic scheme, ZNF469 belongs to 'Disorders of intracellular processes'. The scheme regroups EDS subtypes for which the proteins, coded by the causative genes, function within the same pathway, and which are likely to have shared pathogenic mechanisms, based on current knowledge. However, for EDS subtypes implemented in the Disorders of intracellular processes catagory (subtypes included: Spondylocheirodysplastic EDS and Brittle Cornea Syndrome), the underlying pathophysiological mechanism currently is not readily understood, and classification within this subgroup is provisionary, until further functional information becomes availableCreated: 18 Apr 2017, 11:59 a.m.
From Rare Types, Brady et al., 2017 (PMID:28306225): To provide a comprehensive overview of the clinical phenotype of Brittle Cornea Syndrome, a review of reported cases was undertaken that analysed 51 patients (ZNF469: n=32; PRDM5: n=32), although the the hallmarks of the condition was thin, fragile cornea, with an increased risk for spontaneous corneal rupture, other observed phenotypes such as Craniofacial involvement, Musculoskeletal system, Skin and integument, hearing and cardiovascular were observed less consistently. So currently there is no evidence of a clear genotype–phenotype correlation as all types of mutations scattered across both genes appear to cause indistinguishable clinical phenotypes.Created: 18 Apr 2017, 11:57 a.m.
Comment on list classification: Awaiting expert review on whether this can be made GreenCreated: 7 Apr 2017, 2:21 p.m.
Brittle Cornea Syndrome (BCS) is caused by biallelic mutations in either the genes ZNF469, encoding a zinc finger protein of unknown function, or PRDM5, encoding a DNA- binding transcription factor of the PR/ SET protein family that lacks the intrinsic histon methyltransferase activity. At least one family with a clinical BCS phenotype did not harbor mutations in these genes, suggesting that at least one other gene might be associated with BCS (Rohrbach et al., 2013 PMID:23680354).Created: 7 Apr 2017, 1:16 p.m.
Comment on phenotypes: Added synonymsCreated: 7 Apr 2017, 12:05 p.m.
Comment on mode of inheritance: Added MOI from literatureCreated: 7 Apr 2017, 11:58 a.m.
Comment on publications: Added from 2017 International Classification of the Ehlers–Danlos Syndromes (PMID:28306229) and
The Ehlers–Danlos Syndromes, rare types (PMID:28306225)Created: 7 Apr 2017, 11:52 a.m.
This is a rare recessive form of EDSCreated: 30 Mar 2017, 11:21 a.m.
Phenotypes for gene: ZNF469 were changed from Brittle cornea syndrome 1, 229200; BCS; EDSVIB; Connective Tissue Disorders; Ehlers-Danlos syndrome type VIB; Brittle cornea syndrome to Brittle cornea syndrome 1, OMIM:229200
Source NHS GMS was added to ZNF469. Rating Changed from Green List (high evidence) to Green List (high evidence)
25 July 2017 Panel reviews were assessed, and panel was revised according to reviews and further curation.
This gene has been classified as Green List (High Evidence).
This gene has been classified as Amber List (Moderate Evidence).
ZNF469 was added to Ehlers-Danlos syndromespanel. Sources: Radboud University Medical Center, Nijmegen,Illumina TruGenome Clinical Sequencing Services
Phenotypes for ZNF469 were set to Brittle cornea syndrome 1, 229200; BCS; EDSVIB; Connective Tissue Disorders; Ehlers-Danlos syndrome type VIB;Brittle cornea syndrome
Phenotypes for ZNF469 were set to Brittle cornea syndrome 1, 229200; BCS; EDSVIB; Connective Tissue Disorders; Ehlers-Danlos syndrome type VIB
Publications for ZNF469 were set to 28306229; 28306225; 23680354
Phenotypes for ZNF469 were set to Brittle cornea syndrome 1, 229200; BCS; EDSVIB;Connective Tissue Disorders;
Phenotypes for ZNF469 were set to Brittle cornea syndrome 1, 229200; BCS; EDSVIB;Connective Tissue Disorders;
Phenotypes for ZNF469 were set to Connective Tissue Disorders; Brittle cornea syndrome 1, 229200;BCS;EDSVIB
Mode of inheritance for ZNF469 was changed to BIALLELIC, autosomal or pseudoautosomal
Publications for ZNF469 were set to 28306229;28306225
ZNF469 was created by ellenmcdonagh
ZNF469 was added to Ehlers-Danlos syndromespanel. Sources: Expert list,Emory Genetics Laboratory