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2024
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Genetic testing for macular diseases
Disease Introduction
Stargardt Disease and yellow spots in the fundus are different manifestations of the same disease, characterized by scattered yellow spots visible in the fundus, located in the retinal pigment epithelium layer. When characteristic yellow spots are scattered in the fundus, it is called fundus yellow spot syndrome. When the spots are limited to the posterior pole and accompanied by macular atrophy, it is called Stargardt's disease. The central visual acuity significantly decreases in the early stages of the disease, and color vision disorders appear earlier and gradually worsen. Stargardt disease can be inherited in two ways: autosomal recessive and autosomal dominant.
Introduction and inheritance mode of ABCA4 gene
The ABCA4 gene is located at 1p22, with a total length of approximately 8kb and 50 exons. The cDNA length is 6705bp and encodes 2235 amino acids. It exists in the optic disc membrane of the outer segment of retinal rod cells. The ABCA4 gene encodes a retinal photoreceptor cell specific ATP binding transporter (Rmp) consisting of 2273 amino acids. Patients carrying this gene mutation have lipofuscin (A2E) aggregation in RPE cells, suggesting that ABCA4 may be involved in the transport of retinol molecules between rod cells and RPE, but the specific mechanism is still unclear. ABCA4 gene mutations can cause autosomal recessive inherited RP, Stargardt disease, and cone rod cell malnutrition.
ABCA4 gene mutation type formula
There are over 1356 mutations in the ABCA4 gene included in the HGMD database, of which 66% are missense mutations, 15% are splice mutations, 16% are small fragment insertion deletion mutations, and the proportion of missense mutations is relatively high. In addition to causing STGD1, ABCA4 gene mutations are also associated with a range of other retinal degenerative diseases, such as retinitis pigmentosa (RP), rod cell atrophy (CRD), and age-related macular degeneration (AMD).
Case sharing
Clinical symptoms：The proband is a 24-year-old male with a clinical diagnosis of Stargardt's disease, and his sister also has the same 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.
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) ABCA4 (OMIM 601691) gene mutation often causes retinitis pigmentosa or cone rod cell malnutrition CORD3 or Stargard disease, inherited in an autosomal recessive manner.
(2) The tested proband carries the following heterozygous mutations: 1) ABCA4 c.2063dupA; p.Asn688fs， This mutation has been included in the HGMD database and has been reported as a pathogenic mutation in literature. 2) ABCA4 c.5088C>A; p.Ser1696Arg， This mutation has been included in the HGMD database and has been reported as a pathogenic mutation in literature.
(3) The genetic diagnosis of the subject matches the clinical phenotype, indicating a pathogenic variant.
Genetic counseling advice：(1) The tested parents did not verify the site of this mutation. Suggest genetic counseling.
(2) When the test subject and other patients in the family give birth to a spouse carrying the ABCA4 gene mutation, 50% of the offspring will develop the disease, and 50% of the offspring will be carriers without the disease. The probability of male and female patients developing the disease is equal; When giving birth to a spouse who does not carry the ABCA4 gene mutation, the offspring are 100% carriers of the disease.
First generation verification results：
Reference：
1.Xu (2014) Hum Genet 133, 1255
2. Jiang (2016) Invest Ophthalmol Vis Sci 57: 145 [Additional phenotype]
3. Fujinami (2013) Invest Ophthalmol Vis Sci 54, 6662
4. Carss (2017) Am J Hum Genet 100: 75 [Additional phenotype]
5.Taylor (2017) Ophthalmology 124: 985 [Additional phenotype]
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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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