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2024
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Diseases of lens
Disease Introduction
Congenital cataract (CC) is a congenital eye disease characterized by lens opacity at birth or shortly after birth. The prognosis of congenital cataract is poor, and the cloudy lens can inhibit visual development, which may cause blindness in patients. Congenital cataract is one of the main causes of blindness and amblyopia in children.
The causes of congenital cataracts include metabolic abnormalities, embryonic infections, gene mutations, and chromosomal abnormalities. Genetic factors account for 1/4-1/3 of the causes of congenital cataracts. Cataract can occur independently, be associated with other eye abnormalities, or be part of a multi system genetic disease, accounting for 70%, 15%, and 15% of cataract occurrence, respectively. Hereditary non syndromic cataracts often manifest as autosomal dominant inheritance. With the continuous development of molecular biology technology, a large number of genes related to congenital cataracts have been located. The common mode of inheritance is autosomal dominant inheritance with high penetrance. The known genetic mechanisms of congenital cataracts also include autosomal recessive inheritance and X-linked inheritance.
Introduction and inheritance mode of CRYGC gene
The molecular weight of CRYGC is 21KDa, encoding 173 amino acids. CRYGC encodes gamma crystallin, which plays an important role in crystal development and maintenance of crystal transparency. The CRYGC gene consists of three exons, with the first exon encoding three amino acids and the second and third exons encoding two domains, each consisting of two highly conserved Greek key motifs (GKM). The protein encoded by it accounts for 40% of all mouse crystal proteins and 25% of all human crystal proteins. Gamma crystallin consists of six members, encoded by the gene cluster of human chromosome 2 (CRYGA-F). Only CRYGC (MIM # 123680) and CRYGD encode human abundant gamma crystallin.
CRYGC gene variation types
There are 29 mutations in the CRYGC gene included in the HGMD database, most of which are point mutations or small fragment deletions/insertions. One of the mutation sites has been reported to be associated with primary angle closure glaucoma.
Case sharing
Clinical symptoms：The proband, male, 31 years old, was clinically diagnosed with congenital cataract. The proband's daughter has similar symptoms to the proband, while the other relatives have no related 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) The CRYGC (OMIM 123680) gene mutation often causes congenital cataracts, which are inherited in an autosomal dominant manner.
(2) The tested proband carries the following heterozygous mutations: RYGC c.337C>T; p.Gln113*， This mutation has been included in the HGMD database and has been reported in literature as a highly suspected pathogenic mutation.
(3) The genetic diagnosis of the subject is consistent with the clinical phenotype, and there is a high possibility that the mutation is a pathogenic mutation in the patient.
Genetic counseling advice：(1) The parents and brother of the proband do not carry CRYGC c.337C>T; p. The Gln113 * mutation does not have a related phenotype, while the daughter of the proband carries the mutation and has a related phenotype. When the proband and their spouse have children again, 50% of the offspring will suffer from the disease, and the probability of male and female suffering from the disease is equal.
(2) When the daughter of the proband gives birth to children with a wild-type spouse who does not carry the disease causing gene, 50% of the offspring will develop the disease, and the probability of male and female patients developing the disease is equal.
(3) It is recommended that the proband and their children undergo genetic counseling before giving birth.
First generation verification results：
Reference：
1. Johnson G J, Minassian D C, Weale R A, et al. The epidemiology of eye disease[M]. Arnold, 2003.
2. Foster A, Gilbert C, Rahi J. Epidemiology of cataract in childhood: a global perspective[J]. Journal of Cataract & Refractive Surgery, 1997, 23: 601-604.
3. Bhattacharjee H, Das K, Borah R R, et al. Causes of childhood blindness in the northeastern states of India[J]. Indian journal of ophthalmology, 2008, 56(6): 495.
4. Titiyal J S, Pal N, Murthy G V S, et al. Causes and temporal trends of blindness and severe visual impairment in children in schools for the blind in North India[J]. British journal of ophthalmology, 2003, 87(8): 941-945.
5. Dandona L, Williams J D, Williams B C, et al. Population-based assessment of childhood blindness in southern India[J]. Archives of ophthalmology, 1998, 116(4): 545.
6. Santhiya S T, Kumar G S, Sudhakar P, et al. Molecular analysis of cataract families in India: new mutations in the CRYBB2 and GJA3 genes and rare polymorphisms[J]. Molecular vision, 2010, 16:1837-47.
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