CC2D2A – Joubert syndrome

CC2D2A encodes a coiled-coil and C2 domain–containing protein essential for primary cilium formation and basal body function. Biallelic pathogenic variants in CC2D2A cause Joubert syndrome (JS), an autosomal recessive neurodevelopmental ciliopathy characterized by the “molar tooth sign,” hypotonia, ataxia, global developmental delay, oculomotor apraxia, and variable respiratory dysregulation (PMID:27959436).

Genetic evidence for CC2D2A in JS includes initial reports of compound heterozygous mutations c.2581G>A (p.Asp861Asn) and c.2848C>T (p.Arg950Ter) segregating with disease in a JS family (PMID:27959436). Subsequent large‐scale studies identified CC2D2A variants in 53 unrelated JS patients with biallelic alleles across diverse populations (PMID:36319078). Genotype–phenotype correlation analyses in 209 families show that truncating null alleles preferentially lead to Meckel syndrome, whereas missense and hypomorphic alleles produce JS (20 subjects; PMID:19777577).

The spectrum of CC2D2A variants in JS encompasses missense, nonsense, splice‐site, frameshift, deep intronic, and structural changes, including an exonic LINE‐1 insertion identified by long-read sequencing (PMID:36765129). A representative pathogenic variant is c.2848C>T (p.Arg950Ter), recurrently observed in JS cohorts and linked to severe neurodevelopmental outcomes when homozygous (PMID:27959436).

Phenotypic variability in CC2D2A-related JS includes classic cerebellar vermis hypoplasia with molar tooth sign (HP:0002419), intellectual disability (HP:0001249), global developmental delay (HP:0001263), hypotonia (HP:0001252), ataxia (HP:0001251), and oculomotor apraxia (HP:0000657). Patients with CC2D2A variants also show an increased prevalence of ventriculomegaly and seizures compared with non‐CC2D2A JS cases (p<0.0001 and p=0.024, respectively; PMID:22241855).

Functional studies demonstrate CC2D2A localization at the ciliary basal body with direct interaction with CEP290 (PMID:18950740). In zebrafish, the sentinel CC2D2A ortholog loss‐of‐function causes pronephric cysts—an in vivo model of ciliopathy kidney disease—and genetic interaction with cep290 confirms shared ciliopathy pathways. Patient‐derived iPSC‐based neuronal differentiation models carrying CC2D2A mutations reveal impaired midhindbrain precursor development and defective cilium morphology, recapitulating neural defects in JS (PMID:38502237).

Collectively, over 200 families across multiple studies provide definitive evidence for CC2D2A’s role in JS, satisfying genetic and experimental criteria for a Definitive gene–disease association. Genetic evidence is Strong, with at least 53 probands harboring biallelic CC2D2A variants and confirmed segregation ([PMID:36319078]; [PMID:27959436]). Functional data are Moderate, demonstrating ciliary localization, protein interactions, animal modeling, and patient‐cell phenotypes.

CC2D2A sequencing should be prioritized in JS patients, particularly when ventriculomegaly or seizures are present, and in consanguineous families. This information supports accurate diagnosis, genetic counseling, prenatal testing, and opens avenues for therapeutic interventions targeting hypomorphic alleles.

Key Take-home: Loss-of-function and hypomorphic variants in CC2D2A underlie autosomal recessive Joubert syndrome, with robust genetic and experimental concordance informing diagnosis and family planning.

References

• Molecular Medicine Reports • 2017 • Novel CC2D2A compound heterozygous mutations cause Joubert syndrome. PMID:27959436
• Journal of Medical Genetics • 2012 • Genotype-phenotype correlation in CC2D2A-related Joubert syndrome reveals an association with ventriculomegaly and seizures. PMID:22241855
• American Journal of Human Genetics • 2008 • CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290. PMID:18950740
• Journal of Medical Genetics • 2023 • New insights into CC2D2A-related Joubert syndrome. PMID:36319078

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