Submission Details

The RPGRIP1L gene is located on chromosome 16 at 16q12.2 and encodes the retinitis pigmentosa GTPase regulator-interacting protein (RPGRIP1) -like. It helps control the assembly of the ciliary transition zone, positively regulates proteasomal activity at the ciliary base, and governs autophagy via regulating mTOR signaling. It is ubiquitously expressed at varying levels in all tissues. Multiple disease entities have been reported in association with this gene, but per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in their molecular mechanisms, inheritance pattern, and phenotypic spectrum. Therefore, the following disease entities have been lumped into one disease entity: Joubert syndrome 7 (OMIM:611560), Meckel syndrome 5 (OMIM:611561), and COACH syndrome 3 (OMIM:619113). The preferred disease name suggested for this disorder is autosomal recessive ciliopathy.

RPGRIP1L was first reported in relation to autosomal recessive ciliopathy in 2007 (Delous et al., PMID: 17558409 and Arts et al., PMID: 17558407). The mechanism of pathogenicity appears to be loss of function. Patients with biallelic RPGRIP1L pathogenic variants presented with clinical features consistent with ciliopathies, including neurodevelopmental delay, molar tooth sign on brain MRI, encephalocele, ocular coloboma, oculomotor apraxia, cerebellar ataxia, cystic kidney disease, nephronophthisis, liver disease, and polydactyly.

At least 10 variants (missense, nonsense, frameshift, splice site) have been reported in eight probands in two publications (PMIDs: 17558409, 17558407) included in this curation. The majority of the variants were loss of function variants. Functional data supports the pathogenicity of the missense variants (PMIDs: 17558409, 17558407). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) was reached, considering case-level data.

This gene-disease relationship is also supported by functional studies, expression studies, in vitro assays in non-patient cells, and animal models. RPGRIP1L is expressed in multiple organs, including brain, forelimbs, and kidneys (PMID: 17558409). The encoded protein interacts with another ciliopathy protein, nephrocystin-4 (PMID: 17558409), regulates components of the NPHP modules at the ciliary transition zone, and is essential for the assembly of the transition zone in human embryonic kidney cells (PMID: 29650680). Knockout model organisms recapitulate ciliopathy features including kidney cysts, and central nervous system abnormalities (PMID: 17558409, 29650680). More evidence is available in the literature, but the maximum score for experimental evidence (6 pts.) was reached.

In summary, there is definitive evidence supporting the relationship between RPGRIP1L and autosomal recessive ciliopathy. 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 Kidney Cystic and Ciliopathy Disorders Expert Panel GCEP on the meeting date [April, 24, 2024] (SOP Version 10).