Submission Details

General Description: The SDCCAG8 gene (also known as NPHP10), which encodes a centromeric structural protein (PMID 12559564), was first reported in relation to retinal disease in 2010, in which 12 truncating variants were described in affected individuals with nephronophthisis-related ciliopathies (Otto et al., 2010. PMID 20835237); initial cloning and characterization of the gene occurred in murine tissues in 2003 (murine CCCAP, Kenedy et al., 2003. PMID 12559564). Missense variants in the SDCCAG8 gene were then found in multiple families diagnosed with either Senior-Loken syndrome or Bardet-Biedl syndrome (PMIDs 20835237 and 22190896). SDCCAG8-related ciliopathy is characterized by a broad spectrum of symptoms, including retinal degeneration and nephronophthisis or kidney failure, with or without hypogonadism, respiratory complications and cognitive impairment. To date, studies suggest that, unlike other ciliopathies, SDCCAG8-related ciliopathy notably does not include polydactyly (PMIDs 22626039, 22190896). SDCCAG8-related disease is inherited in an autosomal recessive pattern, with homozygous and compound heterozygous cases described in the literature. Because all cases with different diagnoses exhibit a dominant mode of inheritance and share overlapping phenotypes consistent with a single spectrum of disease, and consistent with criteria outlined by the ClinGen Lumping and Splitting Working Group, these cases have been lumped into a single disease entity, SDCCAG8-related retinopathy.

Summary of Case Level Data (9.2 points): 5 suspected disease-causing variants (4 truncating variants and 1 intronic variant) reported in 4 probands from different countries in 4 publications (PMIDs: 22190896, 20835237, 31534065, 22190896) were scored in this curation. Notably, to date, disease-causing missense variants have not been reported in the literature. All reported variants are deletions, nonsense or splicing variants (for splicing example, see PMID: 22190896). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.

Mechanism for Disease: The mechanism of pathogenicity appears to be loss of function, as multiple nonsense and splicing variants to be disease causing (PMID: 33910785, 24888636) and are characterized in the literature. A single intronic variant has also been reported to be disease causing (ClinVar ID: 60). However, some studies have suggested that missense variants might contribute to oligogenic inheritance of Mendelian ciliopathies (PMID 374231782, 35835773).

Experimental Evidence: 5 POINTS The SDCCAG8 gene product has been extensively studied in murine and cell culture models (PMID 35131266, 35503560). Consistent with a critical role in ciliary formation health, SDCCAG8 is expressed in photoreceptors (PMID 24722439) and is essential for photoreceptor development (PMID 38049871). Multiple cell culture models support the role of SDCCAG8 in cellular ciliary structures, as SDCCAG8 localizes to ciliary structures in vitro (PMIDs 24722439, 27224062).

Summary Statement: In summary, SDCCAG8 is definitively associated with retinal dystrophy; pathogenic variants are associated with autosomal recessive ciliopathy, manifesting in syndromic retinal dystrophy, kidney disease and other variable ciliary phenotypes. The association loss of function variants in SDCCAG8 has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.