RAX2 and Inherited Retinal Dystrophy

The association between RAX2 and inherited retinal dystrophy is supported by multiple lines of evidence. The case report and multi‐patient study (PMID:25789692) demonstrated an autosomal dominant inheritance pattern, with a family in which six members were affected and segregating a novel frameshift mutation. This family‐based evidence shows that the variant leads to a retinal phenotype characterized by declining visual acuity, central scotoma, and characteristic fundus changes. The proband and additional affected relatives (PMID:25789692) provide robust segregation data that support a strong genetic association.

In contrast, independent functional assessment studies have uncovered biallelic RAX2 variants in cases of autosomal recessive inherited retinal dystrophy (PMID:30377383). Five unrelated European index cases with ARRP were identified, with a spectrum of variant types including missense, duplication, and frameshift changes. Protein structure modeling and haplotyping further supported loss‐of‐function as a pathogenic mechanism, widening the molecular spectrum of RAX2‐associated disease.

The genetic evidence is bolstered by detailed variant assessments. The reported variant from the autosomal dominant case, c.465_475del (p.Ala156fs), meets the required HGVS criteria and is emblematic of deleterious mutations in RAX2. Together with the AR evidence showing additional variants such as c.155C>G (p.Pro52Arg) and c.335dup (p.Ala113fs), a diverse mutational landscape has been established. These findings underscore the role of RAX2 in retinal pathology across different inheritance patterns.

Functionally, the data indicate that pathogenicity likely arises through a loss‐of‐function mechanism. In vitro protein modelling and structural assessments within the functional study revealed that missense and truncating variants disrupt conserved domains of the RAX2 transcription factor. These functional perturbations closely mirror the clinical presentations seen in patients, supporting the biological relevance of the variant findings (PMID:30377383).

Despite the observation of two distinct modes of inheritance, the converging genetic and experimental evidence provides a coherent narrative linking RAX2 dysfunction to retinal dystrophy. The autosomal dominant family, with multiple affected members and a clearly segregating frameshift mutation, demonstrates one facet of this association, while the autosomal recessive cases expand the phenotype through biallelic loss‐of‐function events. Clinicians should be aware of this genetic heterogeneity when evaluating patients with central scotoma and related retinal findings.

Key take‑home: RAX2 mutations, whether in a heterozygous or biallelic state, offer significant diagnostic utility in inherited retinal dystrophy, emphasizing the need for comprehensive genetic testing to guide prognosis and management.

References

• JAMA Ophthalmology • 2015 • Autosomal Dominant Retinal Dystrophy With Electronegative Waveform Associated With a Novel RAX2 Mutation PMID:25789692
• Genetics in Medicine • 2019 • Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease PMID:30377383

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