Submission Details

CSPP1 was first reported in relation to autosomal-recessive classical Joubert Syndrome (JBTS) with or without Jeune asphyxiating thoracic dystrophy (JATD) in 28 individuals, and with a Meckel Syndrome (MKS)-like phenotype in 2 individuals from a single family, in three back-to-back publications in 2014 (Akizu et al., PMID:24360807; Tuz et al., PMID:24360808; Shaheen et al., PMID: 24360803). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms AND/OR inheritance pattern AND/OR phenotypic variability. Therefore, the three disease entities have been lumped into one disease entity, Joubert Syndrome 21 (OMIM:615636). There are 31 null variants (variant types: 9 nonsense, 6 splice site, 16 frameshift) that have been reported in >30 probands in at least 7 publications (PMIDs 24360807, 24360808, 24360803, 32386258, 26092869, 27434533, 31980526) and 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 known to be biallelic loss of function. This gene-disease association is also supported by experimental evidence e.g. zebrafish-morpholino, expression studies, and in vitro functional assays with primary patient cells (dermal fibroblasts) (PMIDs 24360807, 24360808, 24360803). Renal involvement in terms of hyperechogenic (oligocystic) kidneys was reported infrequently in a minority of patients (about 3/30). In summary, CSPP1 is definitively associated with a spectrum of autosomal-recessive ciliopathy phenotypes. 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 GCEP on the meeting date 6/23/2021 (SOP Version 8).