Submission Details

RARB is located on chromosome 3 at 3p24.2 and encodes the retinoic acid receptor beta protein. The RARB protein is an important component of the retinoic acid signaling pathway. It forms a heterodimer with RXR proteins which then acts as a transcription factor that binds to certain DNA sequences called retinoic acid response elements (RARE) and, in the presence of the retinoic acid ligand, activates the transcription of specific genes. RARB was first reported in relation to syndromic microphthalmia 12 in 2013 (Srour et al., PMID: 24075189). Syndromic microphthalmia 12 is almost exclusively an autosomal dominant disorder characterized by microphthalmia, coloboma, sclerocornea, diaphragmatic hernia, pulmonary hypoplasia, failure to thrive, developmental delay, motor regression, cognitive impairment, hypotonia, and progressive spasticity. RARB has also been associated with autosomal recessive syndromic microphthalmia 12. However, this is based on only one non-consanguineous family with four affected siblings of whom two were genotyped (PMID: 24075189). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no significant difference in the phenotypic variability and therefore lumped the single family segregating autosomal recessive inheritance with those segregating autosomal dominant inheritance at this time. A total of 12 variants (9 missense, 3 nonsense, and 1 frameshift) that have been reported in 18 probands in eight publications and are included in this curation (PMIDs: 24075189; 27120018; 30480585; 32573669; 31816153; 32737437; 35105264; 35937981) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to include both gain of function and loss of function variants. Specifically, of the 5 missense variants resulting in autosomal dominant disease that were functionally assessed, 4 showed a gain of function effect and 1 showed a loss of function effect. And the 2 variants resulting in autosomal recessive inheritance, one frameshift and one nonsense, showed a loss of function effect. This gene-disease relationship is also supported by mouse knockout models that show phenotypes related to those seen in patients such as postnatal growth retardation, decreased palpebral aperture, cataracts, lower volume density of lung tissue, impaired respiratory function, and impaired learning (PMIDs: 9240560; 9883728; 11074013; 15635054). It is also supported by zebrafish morphants that develop microphthalmia and coloboma (PMID: 31816153). Additionally, STRA6 and ALDH1A3, similar to RARB, also function within the retinoic acid signaling pathway and variants in both genes are known to cause autosomal recessive microphthalmia phenotypes in humans. In summary, RARB is definitively associated with syndromic microphthalmia 12 which primarily shows autosomal dominant inheritance, but may rarely show autosomal recessive inheritance as well. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date 04.25.2023 (SOP Version 9.0).