Genetic counseling is a medical service whose purpose is to provide accurate genetic information. It gives patients and families information about the diagnosis, inheritance pattern, recurrence risk, available tests, and treatment options for genetic diseases, and supports autonomous decision-making. This definition is shared internationally, and the three pillars of genetic counseling are ‘information provision’, ‘psychological support’, and ‘decision-making support’3).
Hereditary eye diseases account for about 43% of congenital visual impairment1). The frequency of chromosomal abnormalities in offspring is about 0.5-1%. Red-green color vision deficiency is one of the most common hereditary eye diseases, occurring in about 5% of males and 0.2% of females. The prevalence of retinitis pigmentosa is about 1 in 4,000 to 1 in 5,000, making it one of the major causes of visual impairment2).
The scope of genetic counseling includes not only the patient with the hereditary disease, but also family members who may develop it and carriers worried about passing it on to future children. Ophthalmologists play a role in diagnosis while working with genetic specialists and certified genetic counselors to provide information.
It can be received in the genetics department of a university hospital or core hospital, or at a facility with certified genetic counselors. Facilities can be found by referring to the lists of certified genetic counselors from the Japan Society of Genetic Counseling and the Japan Society of Human Genetics. The website of the Nanbyo Information Center also provides guidance on where to consult.
The pattern of inheritance is core information in genetic counseling and is classified into four major patterns.
Autosomal dominant inheritance
Onset condition: The disease occurs with a mutation in one allele (heterozygous state).
Pedigree features: Affected members appear in successive generations.
Recurrence risk: The chance of passing it to a child is 50%.
Note: If penetrance is not 100%, a generation may be skipped.
Autosomal recessive inheritance
Onset condition: The disease occurs when both alleles are mutated (homozygous or compound heterozygous).
Pedigree features: Affected members appear among siblings. Parents are usually carriers (heterozygous).
Recurrence risk: The chance of disease in a child born to two carriers is 25%.
Recent trend: Because cousin marriages have become less common, the proportion of compound heterozygotes has increased.
X-linked inheritance
Affected individuals: Most patients are male (hemizygous).
Women: Because they have two X chromosomes, a mutation in one makes them a carrier.
Pedigree features: Affected people are predominantly male, and transmission is from mother to son.
Recurrence risk: The probability that a carrier mother’s son will be affected is 50%.
Maternal inheritance (mitochondrial inheritance)
Feature: Sperm mitochondrial DNA (mtDNA) is broken down almost completely at fertilization. Therefore it is passed only from the mother to the child.
Representative disease: Leber hereditary optic neuropathy (LHON).
Difference from X-linked inheritance: The difference is that female patients also appear.
Heteroplasmy: When normal mtDNA and mutated mtDNA coexist, the phenotype varies.
| Location | Disease name | Inheritance pattern | Causative gene |
|---|---|---|---|
| cornea | gelatinous drop-like corneal dystrophy | autosomal recessive | TACSTD2 (1p) |
| cornea | granular, lattice, and Avellino corneal dystrophy | autosomal dominant | TGFBI (5q) |
| lens | congenital cataract | autosomal dominant (multiple genes) | — |
| lens | Marfan syndrome | autosomal dominant | FBN1 (15q) |
| retina | retinitis pigmentosa | autosomal dominant, autosomal recessive, and X-linked | more than 100 causative genes2) |
| retina | Stargardt disease | autosomal recessive | ABCA4 (1p) |
| retina | juvenile retinoschisis | X-linked | RS1 (Xp) |
| retina | retinoblastoma | autosomal dominant | RB1 (13q) |
| optic nerve | Leber hereditary optic neuropathy | maternal inheritance (mtDNA) | — |
| optic nerve | autosomal dominant optic atrophy | autosomal dominant | OPA1 (3q) |
| color vision | red-green color vision deficiency | X-linked | — |
The inheritance pattern differs. In autosomal dominant inheritance, the chance of passing it from an affected parent to a child is 50%. In autosomal recessive inheritance, if both parents are carriers, the chance that a child will develop the disease is 25%. In X-linked inheritance, the chance that a son of a carrier mother will be affected is 50%, and in maternal inheritance (mitochondrial), if the mother is affected or a carrier, it may be passed to all children. For individual situations, consultation with a genetics specialist or certified genetic counselor is recommended.
The onset mechanisms of hereditary eye diseases are classified by the type of effect a genetic mutation has on protein function.
More than 100 causative genes for retinitis pigmentosa have been identified, and even the same phenotype can be caused by many different genes2). This genetic diversity makes diagnosis difficult.
The following preparation is needed to carry out genetic counseling appropriately.
| Test type | Target | Features |
|---|---|---|
| PCR and Sanger sequencing | Mutation analysis of a single gene | Highly accurate. Suitable for confirming known mutation sites |
| Panel testing (targeted sequencing) | A set of genes associated with specific diseases | Simultaneous search of genes related to retinal diseases. High diagnostic yield5) |
| Exome analysis (NGS) | All exonic regions | Detects unknown variants. Effective when there are many disease-causing genes |
| Whole-genome analysis (WGS) | Entire genome | May have a higher diagnostic yield than existing targeted NGS tests13) |
In hereditary retinal dystrophy, when a disease caused by an RPE65 gene mutation is suspected, and in cases such as when the test is intended to help determine eligibility for gene therapy, some tests that meet the required conditions can be performed as insured medical care4).
Careful judgment is needed when interpreting variants. It is known that about 30% of descriptions published as “variants” in papers are polymorphisms (normal variants). In general, sequence changes that occur in one or more out of every 100 healthy individuals should be treated as polymorphisms.
The following major databases are used.
For some hereditary eye diseases, genetic testing can be provided as insured medical care when the treatment indication is being determined and the designated facility requirements are met. However, coverage depends on the type of test and the disease being tested, so confirmation at the facility you visit is necessary. Tests not covered by insurance may be paid for out of pocket. For designated intractable diseases (such as retinitis pigmentosa), financial support may also be available through the designated intractable disease medical expense subsidy program4).
When providing genetic counseling, collaboration with a genetics specialist and a certified genetic counselor is considered ideal. In university hospitals, review by an ethics committee may be required. Because genetic information can affect not only the patient but also family members, special care is needed in how it is handled. Social discussion is also progressing on preventing unfair discrimination based on genetic information8).
The following inherited eye diseases are designated intractable diseases and are eligible for medical expense support.
For patients with intractable diseases, out-of-pocket medical costs are reduced. A monthly cap is set for the combined total of outpatient care, hospitalization, and prescriptions, and income-based categories are applied.
The gene therapy drug voretigene neparvovec for inherited retinal dystrophy caused by RPE65 gene mutations is a subretinal formulation using an AAV2 vector. Its efficacy and safety have been confirmed in randomized controlled trials6). Deciding whether the treatment is indicated requires confirmation of the disease type through genetic testing.
As for antisense oligonucleotide (ASO) therapy, intravitreal administration of a formulation for Leber congenital amaurosis type 10 (LCA10) caused by CEP290 mutations is being studied in clinical trials9).
Autologous retinal pigment epithelium cell transplantation using iPS cells is being studied as regenerative medicine for age-related macular degeneration7). Although it is a different field from inherited retinal diseases, it is drawing attention as a real example of retinal cell therapy.
For hereditary retinal dystrophy caused by RPE65 mutations, the efficacy and safety of voretigene neparvovec have been shown in RCTs6). To confirm treatment eligibility, the disease subtype must be determined by genetic testing. In LCA10 with CEP290 mutations, intravitreal administration of ASO formulations is being studied in clinical trials9).
Autosomal dominant, autosomal recessive, and X-linked inheritance follow Mendel’s laws. However, the following factors can make simple prediction difficult.
Mitochondria are found in the cytoplasm, and only mtDNA from the mother’s egg is passed on to the child. Each cell contains thousands of copies of mtDNA, and a mixed state of mutant mtDNA and normal mtDNA (heteroplasmy) can occur. The higher the proportion of heteroplasmy, the more severe the symptoms tend to be. In Leber hereditary optic neuropathy (LHON), three variants—11778 (most common), 3460, and 14484—account for about 90% of all variants.
Uniparental disomy is a condition in which both chromosomes of a pair are inherited from the same parent, with no chromosome from the other parent. A child born to a carrier of an autosomal recessive disease may develop the disease even if the other parent is not a carrier, creating an apparent sporadic case10). Along with de novo variants and compound heterozygotes, hereditary disease should be considered even when there is no family history.
