A 28-year-old man presents with progressive night blindness since age 12, followed by gradual peripheral vision loss. Fundoscopy reveals bone-spicule retinal pigmentation, attenuated arterioles, and waxy optic disc pallor. Full-field ERG shows markedly reduced scotopic responses. Genetic testing identifies a heterozygous mutation in the RHO gene (autosomal dominant inheritance), while his unaffected cousin with identical clinical presentation carries a biallelic mutation in USH2A (autosomal recessive). The phenomenon illustrated by **A** in the diagram—where the same clinical phenotype of retinitis pigmentosa results from mutations in different genes—is best described as which of the following?

Explanation

## Why Locus heterogeneity (genetic heterogeneity) is right The clinical anchor is the definition of LOCUS HETEROGENEITY: the SAME CLINICAL PHENOTYPE (retinitis pigmentosa with identical fundoscopic and electrophysiologic findings) is caused by mutations in DIFFERENT GENES at DIFFERENT LOCI. In this case, both the patient (RHO mutation, AD) and his cousin (USH2A mutation, AR) present with indistinguishable RP phenotypes but carry mutations in entirely different genes. This is the hallmark of locus heterogeneity. Retinitis pigmentosa is the classic textbook example, with >100 causative genes (RHO, RPGR, USH2A, CRB1, RP1, EYS, etc.) exhibiting all Mendelian inheritance patterns. The key distinguishing feature is that the LOCUS (gene location) differs, even though the PHENOTYPE is identical. [Kanski Clinical Ophthalmology 9e Ch 13; Harrison 21e Ch 31] ## Why each distractor is wrong - **Allelic heterogeneity**: This refers to DIFFERENT MUTATIONS within the SAME gene (same locus) producing different phenotypes. For example, different CFTR mutations cause classic cystic fibrosis versus CBAVD versus pancreatitis. Here, the mutations are in DIFFERENT genes (RHO vs USH2A), not the same gene, so this is not allelic heterogeneity. - **Variable expressivity**: This describes different clinical SEVERITY or MANIFESTATIONS of the same genotype within a family. Both the patient and cousin have the same clinical severity and presentation, but their genotypes are different (different genes entirely), so variable expressivity does not explain this scenario. - **Incomplete penetrance**: This refers to carriers of a pathogenic mutation who do NOT manifest the disease phenotype. Both the patient and cousin are fully affected with classic RP signs and symptoms, so penetrance is complete (100%) in both cases. This is not the relevant concept. **High-Yield:** Locus heterogeneity = same disease phenotype, many different genes; allelic heterogeneity = same gene, different mutations, different phenotypes. RP is the gold-standard example of locus heterogeneity (>100 genes, all Mendelian patterns). [Kanski Clinical Ophthalmology 9e Ch 13; Harrison 21e Ch 31]