Submission Details

INPP5E was first linked to autosomal recessive Joubert syndrome (JBTS) in 2009 (PMIDs: 19668215, 19668216), although the genomic region was linked to JBTS in 1999 (PMID: 10577920). Biallelic pathogenic variants in INPP5E are associated with JBTS (MIM #213300) and a lesser studied, MORM (mental retardation, truncal obesity, retinal dystrophy and micropenis) syndrome (MIM #610156). While the majority of JBTS-causing variants are missense that occur within the phosphatase domain of INPP5E (PMIDs: 19668216, 23386033, 27434533, 25818971, 29052317, 32139166), a few loss-of-function variants are also reported. Only 2 MORM-related, nonsense variants in the C-terminal CAAX box of the protein (PMIDs: 16493448, 31173343, 34211432), have been described. Functional studies demonstrate that JBTS-causing variants do not affect protein localization but lead to loss of enzymatic activity, while MORM-related variants result in loss of protein localization while retaining enzymatic function (PMID: 19668215). Both diseases also have different clinical presentations - including different organ involvement (PMIDs: 10577920, 16493448). Importantly, MORM syndrome does not have any notable renal manifestations (PMID: 16493448). Therefore, based on criteria established by the Lumping and Splitting working group, the gene disease association of INPP5E has been split and here we specifically describe the relationship between INPP5E and JBTS.
There have been many reports of probands with homozygous recessive or compound heterozygous variants in INPP5E (at least 15 unique gene variants) that lead to JBTS (PMIDs: 19668216, 23386033, 27434533, 25818971, 29052317, 32139166). Within these reports, not all, but many probands also present with renal symptoms including nephronophthisis, cysts and other nephropathy (PMIDs: 25818971, 27434533, 29146704, 29052317, 29230161). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Evidence supporting the gene-disease relationship not only includes genetic case-level data but also experimental data using mouse and zebrafish animal models. These animal models have recapitulated an array of defects observed in JBTS patients including cystic kidneys, cerebellar, skeletal and ocular abnormalities (PMIDs: 19668215, 23022135, 27056978). Further, the animal and cell-based studies have demonstrated the role of INPP5E in regulating PIP3 levels via its 5’ phosphatase function for ciliary maintenance (PMIDs: 27998989, 19668216). Results also demonstrate the ability of WT INPP5E to rescue ciliary defects in cells lacking endogenous enzyme (PMIDs: 19668215, 23022135). The experimental evidence was scored at a total of 5 points. In summary, INPP5E is definitely associated with autosomal recessive JBTS. 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 Cystic and Ciliopathy Disorders GCEP on 09/08/21 (SOP Version 8).