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).