Submission Details

General Description: The CRX gene was first reported in relation to retinal disease in 1994 (Evans et al., 1994 PMID 8162077). Missense variants in the CRX gene, which encodes a homeobox domain transcription factor critical for photoreceptor development (PMID 9390562), were then found in multiple families diagnosed with cone-rod dystrophy, characterized by abnormal color vision (Freund et al., 1997, PMID 9390563 and Swain et al., 1997, PMID 9427255). CRX-related retinal dystrophy is characterized by early adult onset of cone-rod dystrophy. Additionally, multiple cases of CRX-related early onset retinal dystrophy (Leber Congenital Amaurosis; PMIDs: 11748859, 20513135, 24265693 and 9931337) have been described. CRX-related disease is most commonly inherited in an autosomal dominant pattern; however, biallelic pathogenic CRX variants have also been described (PMIDs 20513135, 991337). Broader phenotypes including retinitis pigmentosa (PMID 11139241), rod-cone dystrophy (PMID 33910785), pigmented paravenous retinochoroidal atrophy (PMID 32927963) and adult onset macular dystrophy (PMID 25270190); age of onset and severity of disease appears to be variable. Because most cases with different diagnoses exhibit a dominant mode of inheritance and share overlapping phenotypes consistent with a single spectrum of disease, and consistent with criteria outlined by the ClinGen Lumping and Splitting Working Group, these cases have been lumped into a single disease entity, CRX-related retinopathy.

Summary of Case Level Data (11.5 points): 8 variants suspected disease-causing variants (4 predicted null and 4 missense or other variants) that have been reported in 8 probands in 6 publications (PMIDs: 9792858, 9427255, 20513135, 11748859, 9931337, 9390563) were scored in this curation. De novo and inherited null variants in families from multiple countries were included in the curation (PMID 11748859 and 20513135). However, missense mutations have also been associated with CRX-related disease in multiple publications (PMIDs: 9390563, 9427255, 9931337, 20513135). More evidence is available in the literature.

Mechanism for Disease: The mechanism of pathogenicity appears to be variable, as multiple nonsense and missense variants and full exon or whole gene deletions are reported to be disease causing (PMID: 33910785, 24888636). Missense variants in the homeodomain apparently impact DNA binding variably (PMID 36778408), while truncating variants and experimental data suggest that haploinsufficiency underlies some cases (PMIDs 38049871, 30557390, 27032803). A number of whole gene deletions have also been described to be correlated with a milder, later-onset retinopathy, mimicking age-related macular degeneration. Emerging research may elucidate a more well defined genotype-phenotype correlation, but to date, a genotype-phenotype correlation is under investigation.

Experimental Evidence: 6 POINTS

While the CRX gene product has been extensively studied in murine, cell-culture and human organoid models (PMID 38049871, 35484285, 34653402). Consistent with a critical role in photoreceptor health, CRX is expressed in photoreceptors (PMIDs 19686387, 12949469) and is essential for photoreceptor development (PMID 38049871).

Summary Statement:

In summary, CRX is definitively associated with retinal dystrophy; while pathogenic variants are largely associated with autosomal dominant cone-rod dystrophy, other CRX-related phenotypes have also been described, including recessive disease, early onset retinal dystrophy and later onset macular dystrophy. Though the disease mechanism is likely complex and determined by the properties of a specific variant, the association with retinal dystrophy has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.