Submission Details

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 classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 07.26.2022 (SOP Version 9).