Retinitis Pigmentosa: Inheritance Patterns and Prenatal Testing Options
Inheritance Patterns
Retinitis pigmentosa exhibits extreme genetic heterogeneity with multiple inheritance patterns: autosomal recessive (50-60% of cases), autosomal dominant (30-40%), X-linked recessive (5-15%), and digenic inheritance, with up to 50% presenting as simplex (sporadic) cases where the inheritance pattern is initially unknown. 1, 2, 3
Breakdown by Inheritance Mode
Autosomal recessive RP represents the largest proportion, accounting for approximately 62% of simplex cases when molecularly diagnosed, requiring both parents to be carriers of pathogenic variants in the same gene 2, 4
Autosomal dominant RP accounts for roughly 24% of simplex cases, where a single pathogenic variant from one parent is sufficient to cause disease, though penetrance may be incomplete 2, 5
X-linked recessive RP comprises about 14% of simplex cases, affecting primarily males while females are typically carriers, with multiple loci identified on the X chromosome (XLRP2, XLRP3) 2, 5
Digenic inheritance occurs rarely, where mutations in two different genes are required to manifest disease 1
Genetic Complexity
Over 45 causative genes/loci have been identified for non-syndromic RP, with the RHO (rhodopsin), RP1, and RPGR genes contributing the greatest number of known mutations 1, 3
Approximately 60% of RP cases still have no identified genetic cause despite extensive testing, reflecting the tremendous genetic heterogeneity 1
The same gene can be involved in different inheritance patterns, and different mutations in the same gene may cause different clinical presentations 1, 4
Non-Invasive Prenatal Testing Options
Yes, retinitis pigmentosa can be tested for prenatally without invasive procedures like amniocentesis through preimplantation genetic testing (PGT-M), which tests embryos created through IVF before pregnancy is established, completely avoiding the need for prenatal diagnostic procedures. 6
Preimplantation Genetic Testing for Monogenic Disorders (PGT-M)
PGT-M is indicated when one partner has a monogenic disorder (like autosomal dominant RP), both partners are carriers of the same recessive condition (for autosomal recessive RP), or for X-linked disorders, and requires that the pathogenicity of the gene variant is unequivocal before proceeding 6
The European Society of Human Genetics supports PGT-M for autosomal dominant conditions, autosomal recessive conditions, and X-linked disorders, allowing direct mutation testing for the specific pathogenic variant(s) that the parents carry to prevent transmission to offspring 6
This approach is performed on embryos created through IVF before implantation, eliminating the need for any invasive prenatal diagnostic testing during pregnancy 6
Important Caveats for RP-Specific Testing
Genetic testing for RP requires screening for a large panel of genes due to extreme heterogeneity, with no single mutation accounting for more than 10% of unrelated patients 1
The pathogenic variant(s) must be definitively identified in the affected parent(s) before PGT-M can be performed, as the testing is mutation-specific 6
For simplex cases where inheritance pattern is unknown, comprehensive genetic testing of the affected individual is essential first to determine if the condition is inherited and identify the causative mutation(s) 2
Genetic Counseling Considerations
Genetic counseling is always advised for RP due to the complexity of inheritance patterns and the fact that approximately 40% of cases remain genetically unresolved even with comprehensive testing 1, 3
For families with identified mutations, genetic testing in probands and relatives is helpful for genetic counseling to inform reproductive choices 7
Presymptomatic diagnosis of RP through genetic testing is controversial due to the complexity in phenotype and genetics, and the fact that RP currently has no cure, though this primarily applies to testing of at-risk individuals rather than embryo selection 1
Limitations of Non-Invasive Approaches
PGT-M only screens for the specific known familial mutation(s) and cannot detect de novo mutations or mutations in other RP genes 6
If the causative genetic variant cannot be identified in the family (which occurs in ~60% of RP cases), PGT-M cannot be performed, and traditional prenatal diagnosis would be the only option if desired 1
Cell-free DNA testing from maternal blood (NIPT) is not applicable for most inherited conditions like RP, as it primarily screens for chromosomal abnormalities rather than specific gene mutations 6