Welcome to the Gene Scene! Each week, we will explore a gene from the ACMG Secondary Findings list—genes identified by the American College of Medical Genetics and Genomics as having clear, actionable health implications. These genes are included because they’re linked to serious but preventable or manageable conditions when identified early. Here, we focus on the condition that led to the gene’s inclusion on the list, providing clear, relevant information that supports your clinic. To subscribe to the Gene Scene, contact your local GSL or send a request to info@ambrygen.com. 

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Clinical Phenotype Summary:  

The RPE65 gene is located on chromosome 1p31.3 and encodes the retinoid isomerohydrolase protein. Pathogenic variants in this gene are known to cause a spectrum of retinal diseases including Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP), which are inherited in an autosomal recessive fashion. 

RPE65-related retinal diseases are characterized by: 
•    Progressive visual impairment
•    Profound night blindness
•    Nystagmus

Typical onset is between birth and five years of age. Depending on the age of onset, severity, rate of progression and clinical features, individuals with RPE65 alterations may be given one of several clinical diagnoses, including LCA or RP. Biallelic loss of function has been reported as the mechanism of disease for RPE65-related retinal diseases. 

Clinical Resources:  
•    Understanding Your Results: Exome Secondary Findings

Citations
•    Aoun M,et al. Inherited Retinal Diseases Due to RPE65 Variants: From Genetic Diagnostic Management to Therapy. Int J Mol Sci. 2021 Jul 5;22(13):7207. PMID: 34281261
•    Chung DC, Traboulsi EI. Leber congenital amaurosis: clinical correlations with genotypes, gene therapy trials update, and future directions. J AAPOS. 2009 Dec;13(6):587-92. PMID: 20006823
•    Cideciyan AV. Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapy. Prog Retin Eye Res. 2010 Sep;29(5):398-427. PMID: 20399883
•    Sodi A, et al. RPE65-associated inherited retinal diseases: consensus recommendations for eligibility to gene therapy. Orphanet J Rare Dis. 2021 Jun 4;16(1):257. PMID: 34088339
•    Thompson DA, et al. Genetics and phenotypes of RPE65 mutations in inherited retinal degeneration. Invest Ophthalmol Vis Sci. 2000 Dec;41(13):4293-9. PMID: 11095629
•    Ambry Genetics Gene-Disease Validity Scheme 

Each week, we explore a gene from the ACMG Secondary Findings list—genes identified by the American College of Medical Genetics and Genomics as having clear, actionable health implications. These genes are included because they’re linked to serious but preventable or manageable conditions when identified early. 

To learn more about the ACMG Secondary Findings list, click here

To reach all previous Gene Scene emails, click here.