Genetic and clinical spectra of ciliopathies caused by biallelic variants in CEP120 and CC2D2A
We screened PubMed® for reports of patients harbouring biallelic genetic variants in CEP120 or CC2D2A , accessed the Human Gene Mutation Database (HGMD®) for additional entries and manually curated the genetic and phenotypic data available in order to create a comprehensive database for CEP120 - and CC2D2A -associated disease compliant with Human Genome Variation Society (HGVS) recommendations.
To date, only nine index patients harbouring homozygous or compound heterozygous genetic variants in CEP120 have been reported. 4/9 presented with JBTS, 3/9 with Jeune asphyxiating thoracic dystrophy (JATD), 1/9 with a MKS/oro-facial-digital syndrome (OFD) overlap and 1/9 with tectocerebellar dysraphia with occipital encephalocele (TCDOE) (Table 1 & Figure S2A). In these patients, 14 missense alleles, 3 frameshift alleles and 1 nonsense allele are reported, in different combinations (Table 1 & Table S4 & Figure S2B). Variant p.Ala199Pro alone is found in homozygosis in 3 index patients and in compound heterozygote state in another patient (representing 7/14 missense alleles) (Roosing et al., 2016; Shaheen et al., 2015). The CEP120variant p.Leu712Phe is reported in compound heterozygote state in one patient (Roosing et al., 2016) (MTI-143, Table 1) but population data indicate an allelic frequency of ~0.004 with 2 homozygous individuals in the normal population (https://gnomad.broadinstitute.org/) (Table S4). Although in vitro experiments indicated that this variant impairs the recruitment of Talpid3 to the centrioles, its pathogenicity is questionable (Tsai, Hsu, Liu, Chang, & Tang, 2019).
103 patients from 91 families suffering from CC2D2A -related disease have been reported to date (Tabke 2 & Table S3). Roughly half of the patients suffered from JBTS or Joubert syndrome related disorders (JSRD) (32/103 and 18/103 respectively), with slightly less than half displaying an MKS (40/103) or Meckel syndrome-like (ML) presentation (3/103). Rare cases were described with rod-cone dystrophy (RCD) (4/103), Cogan-type congenital oculomotor apraxia (1/103) or autism-spectrum disease (1/103). In 4 reported cases, the phenotype was not unequivocally described (Figure 1A & Table S3). When considering only the index patients, 83 missense alleles were detected, followed by frameshift (n=60), splice-affecting (n=19) and nonsense (n=16) alleles and rare single AA deletions (n=2) or large insertions/deletions (n=4), including one reported case of retrotransposon insertion (Figure 1B & Table S3). Altogether, 75 different genetic variants have been identified in the 91 reported families (Table S5). CC2D2Avariants p.Glu229del and p.Pro721Ser have been each detected in 1 patient in compound heterozygosis or homozygosis, respectively (Table S3) (Mougou-Zerelli et al., 2009; Otto et al., 2011). The allelic frequency in gnomAD is 0.062 for the former (incl. 528 homozygous individuals) and 0.002 for the latter (incl. 3 homozygous carriers) (Table S5), suggesting that these are hypomorphic alleles rather than fully pathogenic variants (Bachmann-Gagescu et al., 2012).