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Familial exudative vitreoretinopathy
Disease Introduction
A genetic disease mainly characterized by vitreoretinal lesions. This disease is a slowly progressing abnormality in the development of vitreoretinal blood vessels that occurs in both eyes. The severity of the disease varies, and it is rare in clinical practice with significant differences in manifestations. It can be asymptomatic or diagnosed as a secondary eye disease, and is prone to misdiagnosis or missed diagnosis. The clinical characteristics are avascular and proliferative lesions in the temporal peripheral retina, which may be accompanied by intraretinal or subretinal lipid exudates, as well as retinal folds. Mechanized traction may eventually progress to retinal detachment, and even nipple and macular displacement.
FZD4 gene and its inheritance mode
FEVR exhibits genetic heterogeneity and diverse genetic patterns. Currently, six pathogenic genes have been found to be associated with FEVR, including FZD4, LRP5, TSPAN12, NDP, ZNF408, and KIF11 genes. The FZD4 gene is located on human chromosome 11q14.2 and contains two exons, encoding the receptor protein frizzled4 with seven transmembrane regions. This protein belongs to the frizzled family that binds to Wnt ligands, and its extracellular region is the highly conserved cysteine rich domain (CRD) at the N-terminus, which determines the specificity of binding to Wnt ligands. The intracellular region contains the PDZ binding domain of the C-terminal serine-x-valine and the disordered protein binding site of lysine threonine X-X-X-X-tryptophan. Norrin/FZD4 protein activates the Wnt/β - catenin signaling pathway, controls transcription processes, regulates endothelial growth and the entire process of retinal vascular development to maturity. The FZD4 gene is inherited in an autosomal dominant manner.
FZD4 gene variation types
There are 124 variants of the FZD4 gene included in the HGMD database, most of which are point mutations or small fragment deletions/insertions, and a small number are large fragment insertions/deletions.
Case sharing
Clinical symptoms：The proband, male, 5 years old, was clinically diagnosed with familial exudative vitreoretinopathy (FEVR), and there were no related symptoms in the proband's relatives.
Testing items：Genetic testing for ophthalmic genetic diseases (441 genes)
Test method ：Extract genomic DNA from the peripheral blood of the subject, construct a genomic library, capture relevant target gene exons and adjacent intron regions through probe hybridization, and enrich them. The enriched target gene fragments were sequenced using a high-throughput sequencing platform, and Sanger sequencing was used to validate the identified pathogenic variants.
Detection result ：Detect a pathogenic gene mutation that matches the clinical phenotype of the subject.
Note: According to the genetic variation classification criteria established by the American Society for Medical Genetics and Genomics (ACMG), mutations are divided into the following five types, with pathogenic mutations represented by pathogenic mutations; Likely pathogenic refers to a variant that may cause disease; Benign mutation; Like benign refers to a mutation that may be benign; Unknown significance refers to mutations with unclear meanings. AD stands for autosomal dominant inheritance; AR stands for autosomal recessive inheritance; X-linked represents X-linked inheritance.
Genetic analysis：(1) The FZD4 (OMIM 604579) gene mutation often causes FEVR, which is inherited in an autosomal dominant manner.
(2) The following heterozygous mutations were found in the FZD4 gene of the tested proband sample: FZD4 c.205C>T; p.His69Tyr， This mutation site has been included in the HGMD database and has been reported in literature as a pathogenic mutation.
(3) The genetic diagnosis of the proband is consistent with the clinical phenotype, indicating a high possibility of pathogenic mutations.
Genetic counseling advice：(1) After testing, the mother of the proband did not carry the mutation, and the father of the proband carried the mutation. Further determination of the clinical phenotype of the proband's father is needed.
(2) The probability of offspring carrying the FZD4 gene mutation site is 50% when the test subject will marry a spouse who does not carry the mutation site in the future.
First generation verification results：
Reference：
1. Omoto (2004) Ophthalmic Genet 25, 81
2. Kondo (2003) Br J Ophthalmol 87: 1291 [Additional report]
3. Qin (2008) Hum Genet 122: 615 [Functional characterisation]
4. LiY(1992) Am J Hum Genet 51(4):749.754
5. Robitaille J(2002) Nat Genet 32 (2):326-330
6. Yang H(2012) Mol vis l8 2438:2446
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CHIGENOVO Co., Ltd. is an ophthalmic gene therapy company, a national high-tech enterprise focusing on genetic diagnosis of genetic eye diseases and the development of gene therapy drugs. It is committed to providing "one-stop" services for patients with genetic eye diseases.
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