Submission Details

RCBTB1 was first reported in relation to autosomal recessive RCBTB1-related retinopathy in 2016 (Coppietiers et al., PMID: 27486781). 13 affected individuals from 6 families were reported in the initial publication. All had retinal disease, with phenotypes ranging from retinitis pigmentosa to chorioretinal macular atrophy. 7 of the individuals from the initial publication had extra-ocular features, primarily affecting the thyroid, ovary, and/or inner ear. The RCBTB1 gene was therefore associated with the disease entity retinal dystrophy with or without extraocular anomalies (MIM# 617175).

In total, 12 variants (missense, nonsense, and frameshift) that have been reported in 11 probands in 4 publications (PMIDs: 27486781, 33104391, 35057699, 33624564) are included in this curation. A total of 16 affected individuals were reported in those 4 publications. All had retinopathy, and 8/16 (50%) were reported to have one or more extra-ocular feature, such as symptoms affecting the thyroid, ovary, ear, kidney, and/or neurologic system. 4 of these individuals with reported extra-ocular manifestations were from consanguineous families (3 from the same extended family). No clear pattern of extra-ocular features is evident at this time. Therefore, the Retina GCEP has curated this gene for RCBTB1-related retinopathy, as opposed to a syndromic entity. The mechanism of pathogenicity is reported to be LOF (PMID: 31494449). While not counted in this curation, members of the Retina GCEP have observed at least 6 additional patients affected with retinopathy with potentially causative RCBTB1 variants and no other molecular genetic diagnosis on panel testing (unpublished, Invitae; unpublished, Blueprint). Of note, there is a report of 3 individuals from 2 families with heterozygous RCBTB1 variants with Coats disease and/or FEVR (Wu et al., 2016; PMID: 26908610). However, others report that RCBTB1 does not appear to be enriched in FEVR cohorts as compared to controls (Yang et al., 2021; PMID: 33104391). At this time, there is not sufficient evidence to curate this gene for these phenotypes or autosomal dominant inheritance.

This gene-disease association of RCBTB1 with autosomal recessive retinopathy is also supported by experimental evidence including expression studies and in vitro functional assays (PMIDs: 27486781, 34617687). Expression analysis of mRNA shows strong expression in human retina and limited expression in RPE, and RCBTB1 immunoreactivity in the murine retina mainly localized to the inner retina (PMID: 27486781). In addition, RCBTB1 expression reduced in patient RPE compared to control (PMID: 34617687). In cultured RPE cells, RCBTB1 expression reduced in patient RPE compared to control (PMID: 34617687) and morphologic differences (flattened appearance and reduced surface microvillus densities) were observed in cilia in patient-derived RPE cells as compared to control cells (PMID: 34617687).

In summary, RCBTB1 is definitively associated with autosomal recessive RCBTB1-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.