CC2D2A – Joubert syndrome 9

Joubert syndrome type 9 (JBTS9) is an autosomal recessive ciliopathy characterized by intellectual disability (HP:0001249), hypotonia (HP:0001252), oculomotor apraxia (HP:0000657), and variable cerebellar vermis hypoplasia. Neuroimaging reveals a distinctive “molar tooth sign” reflecting mid-hindbrain malformation. JBTS9 falls within a spectrum of Joubert syndrome subtypes, each defined by pathogenic variants in distinct ciliary genes. The prevalence of JBTS is estimated at approximately 1 in 100 000 live births, with JBTS9 accounting for a minority of cases. Clinical heterogeneity includes retinal dystrophy, renal cystic disease, and liver fibrosis in some patients. Accurate molecular diagnosis is therefore essential for prognostication and genetic counseling.

Whole exome sequencing in a consanguineous Pakhtun family identified a novel homozygous missense variant c.4417C>G (p.Pro1473Ala) in CC2D2A, co-segregating with Joubert syndrome 9 in an autosomal recessive pattern and absent in 200 ethnically matched controls ([PMID:32989887]). In silico analyses predict deleterious effects on protein conformation and C2 domain function. Sanger validation confirmed segregation in multiple affected siblings, highlighting the utility of WES in consanguineous populations. This report expands the allelic repertoire of CC2D2A and underscores the need for targeted testing in high-consanguinity settings.

Initial homozygosity mapping in at least 4 unrelated consanguineous families revealed loss-of-function CC2D2A alleles—including nonsense (p.Arg1019Ter) and canonical splice-site (c.2338+1G>C) variants—with segregation confirmed by linkage analysis and Sanger sequencing ([PMID:18950740]). Linkage calculations yielded maximum two-point LOD scores >3.5 in affected sibships. Additional siblings exhibited renal and hepatic involvement, reflecting phenotypic variability. These cases establish CC2D2A as a recurrent cause of JBTS9, with multiple alleles co-segregating in AR pedigrees.

The CC2D2A variant spectrum comprises missense changes (e.g., p.Pro1473Ala), nonsense mutations (e.g., p.Arg950Ter), frameshifts (e.g., p.Ala1577ValfsTer5), canonical splice-site disruptions (c.2338+1G>C), and deep intronic alterations (c.1149+3569A>G). To date, at least 7 distinct pathogenic alleles have been reported across JBTS9 and related ciliopathies, reflecting extensive allelic heterogeneity.

Functional studies demonstrate localization of CC2D2A to the ciliary basal body and physical interaction with the ciliopathy protein CEP290. In zebrafish, loss-of-function “sentinel” cc2d2a mutants develop pronephric cysts, and concurrent knockdown of cep290 produces synergistic cystogenesis, mirroring human renal phenotypes ([PMID:18950740]). These data implicate CC2D2A in cilium assembly and highlight extragenic modifier interactions.

Collectively, genetic and experimental evidence robustly support a strong association between biallelic CC2D2A variants and autosomal recessive JBTS9. This integrated framework informs diagnostic panel design, enables precise molecular diagnosis, and guides genetic counseling. Key take-home: Biallelic CC2D2A variants underlie Joubert syndrome 9 with concordant functional phenotypes in model systems.

References

• The journal of gene medicine • 2021 • Whole exome sequencing identified a novel missense alteration in CC2D2A causing Joubert syndrome 9 in a Pakhtun family. PMID:32989887
• American journal of human genetics • 2008 • CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290. PMID:18950740

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