Purpose

To describe phenotypic, genotypic, and histopathological features of inherited retinal dystrophies associated with the CRX gene (CRX-RDs).

Design

Retrospective multicenter cohort study including histopathology.

Subjects

Thirty-nine patients from 31 families with pathogenic variants in the CRX gene.

Methods

Clinical data of 152 visits were collected from medical records. The median follow-up time was 9.1 years (interquartile range (IQR), 3.3-15.3 years; range, 0.0-48.8 years). Histopathologic examination of the eye of a 17-year-old patient with advanced early-onset CRX-RD was performed.

Main outcome measures

Visual acuity, retinal imaging, electroretinography, genotype-phenotype correlation, and histopathological examination were evaluated.

Results

The age at onset ranged from birth to the eighth decade of life. Median visual acuity was 1.00 logarithm of the minimum angle of resolution (logMAR) (IQR, 0.69-1.48 logMAR; range, 0.06-3.00 logMAR) at a mean age of 52.0 ± 19.9 years (range, 4.6-81.9 years). Sufficient imaging was available for 36 out of 39 patients (92.3%), and all showed degeneration of at least the macula. Of these 36 patients, 22 (61.1%) had only macular dystrophy. Another 10 patients (27.8%) had additional degeneration beyond the vascular arcades, and 4 patients (11.1%) panretinal degeneration. Two patients (5.1%) had Leber congenital amaurosis. In total, 21 different disease-associated heterozygous CRX variants were identified (10 frameshift, 7 missense, 2 deletion, 1 nonsense, 1 deletion-insertion variants). Missense variants in the CRX homeodomain and 2 variants deleting all functional domains, thus causing haploinsufficiency, generally tended to cause milder late-onset phenotypes. Histopathologic examination of the eye of a 17-year-old patient with advanced early-onset retinal dystrophy due to a heterozygous deletion of exons 3 and 4 of the CRX gene revealed loss of laminar integrity and widespread photoreceptor degeneration especially in the central retina, with extensive loss of photoreceptor nuclei and outer segments.

Conclusions

This study illustrates the large clinical and genetic heterogenic spectrum of CRX-RDs, ranging from Leber congenital amaurosis to mild late-onset maculopathy resembling occult macular dystrophy. Haploinsufficiency and missense variants tended to be associated with milder phenotypes. Patients showed degeneration predominantly affecting the central retina on imaging. The histopathological findings also mirror these clinical findings and features similar to previously reported animal models of CRX-RDs.

Financial disclosure(s)

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.