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Disease Introduction
Corneal DystrophyIt is a general term for a group of progressive corneal lesions with genetic heterogeneity, characterized by loss of corneal transparency and visual impairment. According to anatomical location, it can be divided into superficial corneal malnutrition, anterior elastic layer corneal malnutrition, stromal corneal malnutrition, posterior elastic layer and corneal endothelial malnutrition. Autosomal dominant inheritance is the main mode of inheritance for corneal malnutrition. To ensure the safety of corneal refractive surgery, in clinical practice, when receiving patients with corneal malnutrition, the classification of their disease should be clarified before deciding whether to undergo surgery.
TGFBI gene and its inheritance mode
The TGFBI gene (transforming growth factor B induced gene) is located in the 5q31 region of the human chromosome. The TGFBI gene contains 17 exons, encoding 683 amino acids. The TGFBI gene is mainly inherited in an autosomal dominant manner. So far, a total of 33 genetic mutations have been found in families with corneal malnutrition. The product expressed by TGFBI gene is called corneal epithelial protein (KE protein). KE protein is closely associated with laminin, fibronectin, and collagen I in the extracellular matrix, and is somewhat associated with collagen II and VI, but less associated with collagen IV. KE protein may induce apoptosis by abnormal interaction with one of the proteins through apoptosis promoting factor caspase-3. KE protein mainly participates in regulating cell apoptosis through two amino acids, Asp and Ile, in the fasc2 and fasc4 regions. Overexpression of KE protein will disrupt this process, leading to deposition of denatured products and repeated epithelial erosion.
TGFBI gene mutation types
There are 72 mutations in the TGFB1 gene included in the HGMD database, almost all of which are point mutations or small fragment deletions/insertions. Currently, no large fragment insertions have been found. Malnutrition associated with TGFBI gene mutations includes Avellino corneal malnutrition I, granular corneal dystrophy (GCD), Reis-B ü cklers corneal malnutrition (RBCD), Thiel Behnke corneal malnutrition (TBCD), and lattice corneal dystrophy (LCD).
Case sharing
Clinical symptoms：The proband, male, 18 years old, was clinically diagnosed with corneal malnutrition. The proband's relatives have no relevant symptoms.
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) TGFBI (OMIM 601692) gene mutations often cause corneal malnutrition, which is inherited in an autosomal dominant manner.
(2) The following heterozygous mutations were found in the TGFBI gene of the tested proband sample: TGFBI c.371G>A; p.Arg124His， 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) The tested parents did not verify the site of this mutation. Suggest family genetic counseling.
(2) The probability of offspring carrying the TGFBI gene mutation is 50% when the test subject will marry a spouse who does not carry the gene mutation in the future.
First generation verification results：
Reference：
1. Skonier J(1992) Cell Biol 11,511-522．
2. Billings P C(2000) Bid Chem 275:309-315．
3. Munier (1997) Nat Genet 15, 247
4. Konishi (1998) Am J Ophthalmol 126: 450 [Additional phenotype]
5. Munier (2002) Invest Ophthalmol Vis Sci 43: 949 [Additional report]
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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