INPP5E

Inheritance Pattern: AR

Disease ID:MONDO:0012423

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0012423

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0008996

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0018772

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0016364

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012423

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0012423

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0008944

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0008944

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0012423

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0008944

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0008944

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0012423

Submitter: ClinGen

The *INPP5E* gene is located on chromosome 9 at 9q34.3 and encodes Inositol polyphosphate-5-phosphatase, which hydrolyzes Ins(1,4,5)P3, in turn mobilizing intracellular calcium and acting as a second messenger mediating cell responses to various stimulation. *INPP5E* was first reported in relation to autosomal recessive Joubert syndrome (Bielas et al., 2009, PMID:19668216) and autosomal recessive MORM (mental retardation, truncal obesity, retinal dystrophy and micropenis) syndrome (Jacoby et al., 2009, PMID:19668215), although the loci were linked in 1999 (Saar et al., PMID:10577920) and 2006 (Hampshire et al., PMID:16493448) respectively. Joubert syndrome is characterized by a ‘molar tooth sign’ of the midbrain-hindbrain junction, retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly (PMID:10577920), while MORM syndrome is associated with intellectual disability, truncal obesity, retinal dystrophy and micropenis, without renal manifestations (PMID:16493448). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, while there was no difference in inheritance patterns, there were differences in molecular mechanisms and distinct clinical presentation for each. The majority of variants associated with Joubert syndrome are located in the phosphatase domain (PMID 19668216; Travaglini et al., 2013, PMID:23386033; Suzuki et al., 2016, PMID:27434533; Devi et al., 2020, PMID:32139166). To date, only two nonsense variants in the C-terminus CAAX domain of *INPP5E* have been described in MORM syndrome (PMID:19668215; Khan et al., 2019, PMID 31173343; Torkar et al., 2021, PMID:34211432). Molecular mechanisms differ in that Joubert syndrome variants result in loss of enzymatic activity without defects in ciliary location (PMID:19668216), while MORM syndrome variants result in loss of membrane localisation while retaining enzymatic activity (PMID:19668215). Therefore, the disease entities have been split into two disease entities, Joubert syndrome (OMIM 213300) and MORM syndrome (OMIM 213300). The curation for autosomal recessive Joubert syndrome has been curated separately by the Kidney cystic and ciliopathy disorders GCEP. Evidence supporting the gene-disease relationship for *INPP5E*-associated MORM syndrome includes case-level data, segregation data, and experimental data. Only two nonsense variants in *INPP5E* have been reported in probands in 3 publications (PMIDs:16493448, 31173343, 34211432) and are included in this curation. The *INPP5E* presumed Pakistani founder variant segregated with disease in 13 other family members in one study (PMID:16493448) and 8 additional family members in another study (PMID:31173343). This gene-disease relationship is supported by experimental evidence showing improper localisation of MORM variants (PMID:19668215; Thomas et al., 2014, PMID:24166846) and the ability of WT *INPP5E* to rescue ciliary defects (PMID:19668215). In summary, there is moderate evidence to support the gene-disease relationship of *INPP5E* and MORM syndrome. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the ClinGen Syndromic Disorders Gene Curation Expert Panel on 07.26.2022. It was reevaluated on 02.05.2025. There was no new evidence. As a result of this reevaluation, the classification did not change.

Inheritance Pattern: AR

Disease ID:MONDO:0008944

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0008944

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0012423

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0008944

Submitter: ClinGen

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).