Meckel Syndrome, Type 4

A number sign (#) is used with this entry because of evidence that Meckel syndrome type 4 (MKS4) is caused by homozygous or compound heterozygous mutation in the CEP290 gene (610142) on chromosome 12q21.

Description

Meckel syndrome is an autosomal recessive pre- or perinatal lethal disorder characterized by a combination of renal cysts and variably associated features including developmental anomalies of the central nervous system (typically occipital encephalocele), hepatic ductal dysplasia and cysts, and postaxial polydactyly (summary by Baala et al., 2007).

For a more complete phenotypic description and information on genetic heterogeneity of Meckel syndrome, see MKS1 (249000).

Clinical Features

Frank et al. (2008) reported a consanguineous family of Kosovar Albanian origin in which 2 male fetuses were found to have ultrasonographic features of Meckel syndrome. Both pregnancies were terminated. Postmortem examination showed enlarged cystic dysplastic kidneys, hepatobiliary ductal plate malformation, postaxial polydactyly, and occipital meningoencephalocele with massively malformed brain. Two fetuses from a second consanguineous family of Kosovar origin were similarly affected.

Mapping

By genomewide analysis of a family with Meckel syndrome, Frank et al. (2008) found linkage to a 3.2-Mb region on chromosome 12q21.31-q21.33 (lod score of 4.32).

Molecular Genetics

Meckel Syndrome

To identify new Meckel syndrome loci, Baala et al. (2007) performed a genomewide linkage scan in 8 families unlinked to known Meckel syndrome loci and found linkage to chromosome 12. The interval was narrowed to an 8-Mb region containing the CEP290 gene which, in view of the phenotypic overlap between Joubert syndrome (213300) and Meckel syndrome, and the finding of Baala et al. (2007) of allelism of these 2 phenotypes at the MKS3 locus (607361), was considered an excellent candidate gene. Sequencing of the 53 coding exons revealed homozygous truncating mutations in 3 families and compound heterozygous mutations in a fourth family (see, e.g., 610142.0008-610142.0010), confirming that CEP290 is the gene for Meckel syndrome on chromosome 12. Sequencing of 20 additional MKS cases, all negative for mutations in the MKS1 gene (609883) and TMEM67 (609884), identified 2 additional MKS-affected families with affected individuals carrying compound heterozygous mutations of CEP290.

Frank et al. (2008) identified a homozygous mutation in the CEP290 gene (610142.0012) in 4 fetuses with Meckel syndrome type 4 from 2 consanguineous families of Kosovar origin. Haplotype analysis indicated a founder effect.

Meckel-like Cerebrorenodigital Syndrome

Baala et al. (2007) also identified CEP290 mutations in 4 families presenting a cerebrorenodigital syndrome, with a phenotype between that of Meckel syndrome and Joubert syndrome and thus representing the continuum of the clinical spectrum between these 2 disorders.