CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype-phenotype correlation

Area of Science:

• Genetics
• Developmental Biology
• Medical Genetics

Background:

• Meckel-Gruber syndrome (MKS) and Joubert syndrome (JBS) are lethal and viable ciliopathies, respectively, with overlapping features.
• Both MKS and JBS are autosomal recessive disorders linked to mutations in various ciliopathy genes.
• CC2D2A mutations were previously identified in both MKS and JBS, suggesting allelism.

Purpose of the Study:

• To investigate the role of the CC2D2A gene in Meckel-Gruber syndrome and Joubert syndrome.
• To identify novel mutations in CC2D2A in patients with MKS and JBS.
• To explore genotype-phenotype correlations within the CC2D2A ciliopathy spectrum.

Main Methods:

• Genetic analysis of the CC2D2A gene in a cohort of fetuses diagnosed with MKS.
• Mutation screening of CC2D2A in patients with a clinical diagnosis of JBS.
• Correlation of identified CC2D2A mutations with clinical and imaging findings.

Main Results:

• Identified 14 novel truncating CC2D2A mutations in 11 MKS cases, confirming CC2D2A's significant role in MKS.
• Detected three missense CC2D2A mutations in two JBS cases.
• Observed a correlation between mutation type and clinical outcome: null alleles associated with MKS, missense mutations with JBS.

Conclusions:

• CC2D2A is a major contributor to Meckel-Gruber syndrome, with null mutations leading to the lethal phenotype.
• Missense or hypomorphic CC2D2A mutations are associated with the neurological disorder Joubert syndrome.
• These findings support phenotype-genotype correlations in CC2D2A-related ciliopathies, distinguishing MKS from JBS based on mutation type.