CRB1

Inheritance Pattern: AR

Disease ID:MONDO:0013453

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0010818

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0008246

Submitter: G2P

Inheritance Pattern: Unknown

Disease ID:MONDO:0008246

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0013453

Submitter: Natera

Inheritance Pattern: AD

Disease ID:MONDO:0008246

Submitter: ClinGen

The *CRB1* gene was first reported in relation to ocular disease in 1999, in affected members from a family with autosomal recessive inheritance who were diagnosed with retinitis pigmentosa 12 (PMID: 10373321). The spectrum of disease with autosomal recessive inheritance subsequently expanded to include cases diagnosed as Leber congenital amaurosis 8 or Coats-like exudative vasculopathy (PMID: 11389483). Cases with autosomal dominant inheritance also emerged in 2005 with the publication of a family with members diagnosed with pigmented paravenous retinochoroidal atrophy (McKay et al., PMID: 15623792). Family members with pigmented paravenous retinochoroidal atrophy exhibited variable expressivity of clinical features including paravenous chorioretinal atrophy, bone spicule pigmentation, optic disc drusen, loss of visual acuity after age 30 years, and/or decreased rod electroretinogram amplitudes. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the pigmented paravenous retinochoroidal atrophy cases were distinguishable from autosomal recessive cases by their mode of inheritance, the scarcity of additional affected families following the initial report, and the absence of evidence of affected status among heterozygous carriers from the autosomal recessive pedigrees. Therefore, cases caused by inherited *CRB1* variants have been split into two separate disease entities, with the present curation focusing on autosomal dominant cases. Two suspected disease-causing variants were scored as part of this curation (both missense), which have been reported in two total families (PMID: 15623792, PMID: 40623937). The variants both show high frequencies among control individuals in the gnomAD database, and functional characterization of their potential mechanism of pathogenicity has not been performed. At least one reported family had multiple affected individuals who were heterozygous for the suspected disease-causing variant, but they were not sufficient in number to contribute to the scoring of the gene-disease relationship through segregation evidence (PMID: 15623792). This gene-disease association is supported by evidence that *CRB1* is highly specifically expressed in the human retina and to a lesser extent in the retinal pigment epithelium, the optic nerve, and the brain (PMID: 30239781). CRB1 protein localizes to the subapical cell surfaces of rod, cone, and Müller glial cells in order to maintain adherens junctions, regulate apical-basal polarity, and modulate apical membrane size in collaboration with the cadherin-catenin complex (PMID: 760678,7 PMID: 28424578, PMID: 32817065). Animal models of biallelic *CRB1* loss-of-function show ocular or photoreceptor dysfunction, but their relevance to autosomal dominant human disease is unclear (PMID: 28306104, PMID: 39965731, PMID: 32817065, PMID: 12915475). In summary, *CRB1* has a Disputed association with autosomal dominant pigmented paravenous retinochoroidal atrophy. This assertion has been found in at least 2 publications but has very limited segregation and proband evidence accumulated over the past 20 years since the initial report, as well as questions about the potential for the variants to be disease-causing. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on July 2nd, 2026 (SOP Version 12).

Inheritance Pattern: AR

Disease ID:MONDO:0020242

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0010818

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0013453

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0008246

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0019118

Submitter: ClinGen

The *CRB1* gene was first reported in relation to ocular disease in 1999, in affected members from a family with autosomal recessive inheritance who were diagnosed with retinitis pigmentosa 12 (den Hollander et al., PMID: 10373321). The spectrum of disease subsequently expanded to include cases diagnosed as Leber congenital amaurosis 8 or RP with Coats-like exudative vasculopathy (PMID: 11389483), or isolated macular disease (PMID: 29391521). Affected individuals generally exhibit retinal features including night blindness, progressive loss of visual acuity, peripheral visual field constriction, photophobia, pigmentary retinopathy with para-arteriolar preservation, central thinning of the outer nuclear layer, hypermetropia, drusen, vascular sheathing, and/or cystoid macular edema. A family was subsequently identified with pigmented paravenous chorioretinal atrophy showing autosomal dominant inheritance (PMID: 15623792). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the cases diagnosed with retinitis pigmentosa 12 or Leber congenital amaurosis 8 shared a recessive mode of inheritance and biallelic loss-of-function mechanism, with overlapping phenotypes that were consistent with a single spectrum of disease. The autosomal dominant cases were distinguishable by their mode of inheritance, the scarcity of additional affected families following the initial report, and the absence of evidence of affected status among heterozygous carriers from the autosomal recessive pedigrees. Therefore, cases caused by inherited *CRB1* variants have been split into two separate disease entities, with the present curation focusing on autosomal recessive cases referred to as *CRB1*-related retinopathy. Fifteen suspected disease-causing variants were scored as part of this curation (seven missense, one in-frame deletion, three frameshift, three nonsense, and one predicted to disrupt splicing). These variants have been collectively reported in ten probands in three publications (PMID: 10373321, PMID: 11231775, PMID: 22065545). The variant types indicate that the mechanism of pathogenicity is biallelic loss-of-function. At least one reported family had a large number of affected individuals who were homozygous for the suspected disease-causing variant, contributing to the scoring of the gene-disease relationship through segregation evidence. This gene-disease association is also supported by evidence that *CRB1* is highly specifically expressed in the human retina and to a lesser extent in the retinal pigment epithelium, the optic nerve, and the brain (PMID: 30239781). CRB1 protein localizes to the subapical cell surfaces of rod, cone, and Müller glial cells in order to maintain adherens junctions, regulate apical-basal polarity, and modulate apical membrane size in collaboration with the cadherin-catenin complex (PMID: 760678,7 PMID: 28424578, PMID: 32817065). Mutations in the *Drosophila* ortholog *crumbs* result in embryonic lethality associated with morphological abnormalities, cell death of epithelial tissues, and overactivation of autophagy in the eye leading to neurodegeneration (PMID: 28306104, PMID: 39965731). *Crb1* loss-of-function in zebrafish results in retinal dystrophy with enhanced rod sensitivity to damage by white light and loss of cone sensitivity to bright white light (PMID: 32817065). Homozygous *Crb1* loss-of-function in mice causes congenitally short photoreceptor inner and outer segments, as well as retinal folds associated with retinal spotting and regions of photoreceptor degeneration (PMID: 12915475). In summary, CRB1 has a Definitive association with *CRB1*-related retinopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on March 5th, 2026 (SOP Version 12).

Inheritance Pattern: AR

Disease ID:MONDO:0013453

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: AD

Disease ID:MONDO:0005514

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0018998

Submitter: Orphanet