Genotype-phenotype correlations in disease caused by mutations in CC2D2A
Having now systematically assessed the variants in CC2D2A and the associated phenotypes for all 103 reported patients, we wondered whether truncating variants (nonsense or frameshift) were associated with a more severe phenotype than missense variants, as suggested before (Mougou-Zerelli et al., 2009). Biallelic truncating variants were found in 66% (21/32) of cases presenting with MKS or ML, contrasting with only 3% (1/40) of cases presenting with JBTS or JSRD (Fisher’s exact test: p<0.0001). Conversely, biallelic missense variants were detected in only 22% (7/32) of MKS/ML cases vs. 53% (21/40) of cases with JBTS/JSRD (Fisher’s exact test: p=0.0143) (Figure 1C & Figure 1D). This systematic analysis of all reported cases to date shows a robust correlation between the type of CC2D2A mutation and the severity of the disease. What is more, we assessed systematically the cases reported in literature with specific mention of either presence or absence of kidney disease and we show that biallelic truncating variants were more frequently found in presence of kidney disease (50%, 20/40) than in cases without kidney involvement (3%, 1/32) (Fisher’s exact test: p<0.0001), in line with the notion that missense changes are more frequently associated with a pure JBTS presentation without extra-CNS manifestations (Figure 1E & Figure 1F). Similar associations were not seen for CEP120 but a meaningful analysis was precluded by the low patient numbers (Figure S2C & Figure S2D).