Retinal disorders

Gene: CRB1

Comment on phenotypes: Previously:
Leber Congenital Amaurosis;Retinitis pigmentosa-12, autosomal recessive, 600105Leber congenital amaurosis 8, 613835Pigmented paravenous chorioretinal atrophy, 172870;Eye Disorders;Retinitis pigmentosa;Retinitis Pigmentosa, Recessive;Retinitis pigmentosa-12, autosomal recessive, 600105

Created: 3 Aug 2021, 2:49 p.m. | Last Modified: 3 Aug 2021, 2:49 p.m.

Panel Version: 2.195

Green List (high evidence)

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Leber congenital amaurosis 8; Retinitis pigmentosa-12; autosomal recessive

Variants in this GENE are reported as part of current diagnostic practice

Comment on mode of inheritance: Changed from 'both' to biallelic, after feedback from Chris Campbell: "As far as I can see there is only 1 variant which has been reported to cause CRB1 related pigmented paravenous chorioretinal atrophy; c.484G>A p.(Val162Met). There are 2 reports on HGMD (McKay et al (2005) Pigmented Paravenous Chorioretinal Atrophy Is Associated with a Mutation within the Crumbs Homolog 1 (CRB1) Gene Invest Ophthalmol Vis Sci. 46:322-328, O’Sullivan et al A paradigm shift in the delivery of services for diagnosis of inherited retinal disease) the second being from our research group describing the first patient in whom we have identified the Val162Met. We have seen this variant a total of 4 times in the het state at the GDL, none of these cases had a diagnosis of Pigmented Paravenous Chorioretinal Atrophy, all were ADRP, with the exception of 1 patient who had a confirmed diagnosis of Usher syndrome (two pathogenic GPR98 mutations identified). The evidence in the McKay et al (2005) is weak with variable expressivity shown, and no functional work was carried out. The valine at codon 162 is only moderately conserved and a methionine is present at this position in two other mammalian species. In silico analysis predicts that this change is unlikely to have a damaging effect on the CRB1 protein. Furthermore, this change is also reported on ExAC browser with a minor allele frequency of 0.12% [144 / 120662] in control populations (0.16% [105/ 66400],including 1 homozygote in the non-Finnish European control population ), which is higher than that expected for a dominant mutation. For other GDL patients in whom single CRB1 changes have been identified only the identified changes have previously been reported in the hom/compound het state in patient with early onset RP/LCA. So represent either part of the diagnosis for the patient (i.e another CRB1 mutation not specified by our test) or a carrier finding. None of these patients had a diagnosis of Pigmented Paravenous Chorioretinal Atrophy. In conclusion I don’t think we should have CRB1 as a dominant gene and the MOI should be AR."

Created: 12 Apr 2017, 9:11 a.m.

This gene is on the Manchester Genetic Retinal Degeneration Conditions panel (covers known genes for isolated progessive retinal degeneration, Leber congenital amaurosis, macular dystrophy, achromatopsia, congenital stationary night blindness as well as the two most common causes of syndromic blindess Usher and Bardet-Biedl syndromes and additional syndromes including Joubert, Senior-Loken, and Cohen syndrome.

Created: 2 Jun 2016, 8:04 a.m.

UKGTN source has Leber congenital amaurosis 8 and Retinitis pigmentosa 12, RP12 as autosomal recessive, and Pigmented paravenous chorioretinal atrophy as autosomal dominant.

Created: 26 Apr 2016, 12:39 p.m.