CC2D2A – Meckel Syndrome

CC2D2A encodes a coiled-coil and C2 domain-containing protein localized to the primary cilium transition zone. Biallelic CC2D2A variants cause autosomal recessive Meckel syndrome (MKS), a perinatally lethal ciliopathy characterized by encephalocele, polydactyly, and cystic renal dysplasia. Genetic testing for CC2D2A is indicated in fetuses or neonates presenting with the classic MKS triad.

Clinical Validity and Genetic Evidence

Initial linkage in 10 nonrelated affected fetuses established CC2D2A as MKS6 (PMID:18513680). Subsequent analysis of 29 MKS families identified multiple novel CC2D2A alleles, including both truncating and missense variants, confirming allelic heterogeneity (PMID:19466712). A Japanese girl with MKS harbored a deep intronic variant (c.1149+3569A>G) and an exonic LINE-1 insertion, both leading to aberrant splicing and frameshifted transcript (PMID:36970932). Example recurrent coding variant: c.1762C>T (p.Gln588Ter).

Variant Spectrum and Inheritance

MKS-associated CC2D2A alleles include loss-of-function (nonsense, frameshift, splice-site) and missense variants affecting conserved domains. Inheritance is autosomal recessive, with biallelic pathogenic variants observed in at least 11 unrelated probands (PMID:18513680; PMID:36970932).

Functional and Experimental Evidence

Patient fibroblasts lack primary cilia on immunofluorescence staining, implicating CC2D2A in cilium assembly (PMID:18513680). Urine-derived cell assays demonstrated retention of a 149-bp intronic fragment and marked reduction of CC2D2A protein in the deep intronic/LINE-1 case (PMID:36970932). In zebrafish, sentinel (cc2d2a) null mutants develop pronephric cysts analogous to human renal dysplasia, confirming a loss-of-function mechanism (PMID:18950740).

Integration and Clinical Utility

Collectively, genetic and functional data provide definitive evidence that autosomal recessive loss of CC2D2A function underlies Meckel syndrome. Comprehensive sequencing, including intronic and transposon detection, maximizes diagnostic yield. Identification of pathogenic alleles informs prenatal counseling, recurrence risk, and future therapeutic strategies targeting aberrant splicing.

Key Take-home: Biallelic CC2D2A variants are a definitive cause of autosomal recessive Meckel syndrome; integrated genetic and functional assays are essential for accurate diagnosis.

References

• American journal of human genetics • 2008 • Identification of CC2D2A as a Meckel syndrome gene adds an important piece to the ciliopathy puzzle. PMID:18513680
• Human mutation • 2009 • Mutation spectrum of Meckel syndrome genes: one group of syndromes or several distinct groups? PMID:19466712
• American journal of human genetics • 2008 • CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290. PMID:18950740
• Annals of human genetics • 2023 • Identification of pathogenic deep intronic variant and exonic LINE-1 insertion in a patient with Meckel syndrome. PMID:36970932

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