Meckel Syndrome and Related Disorders

Abstract

Cilia‐related disorders (ciliopathies) are characterised by great clinical and genetic heterogeneity and overlaps between different disease entities. Meckel syndrome (MKS) is generally allelic to Joubert syndrome and related disorders, and resides at the severe end of the broad phenotypic spectrum of ciliopathies. MKS is a usually autosomal recessive, multisystemic disorder of early developmental rather than degenerative nature. Classic disease manifestations comprise occipital meningoencephalocele, cystic kidneys, hepatobiliary ductal plate malformation and postaxial polydactyly, whereas several other additional features such as heart defects and cleft lip/palate have also been reported. Survival beyond birth or the neonatal period is unusual with the vast majority of cases dying in utero. Until recently and before next‐generation sequencing (NGS) have emerged, molecular genetic testing of MKS and related ciliopathies was considerably hampered by its extensive locus heterogeneity. However, NGS‐based technologies make genetic testing now possible and have revolutionised research and diagnostics. For example, specific disease panels that allow sequencing of all disease genes in parallel significantly improve genetic diagnostics and lead to reduction of turnaround times and costs. Key Concepts: Meckel syndrome (MKS) resides at the severe end of the broad phenotypic spectrum of cilia‐related disorders (ciliopathies). MKS and other ciliopathies are clinically and genetically heterogeneous. MKS is a usually autosomal recessive, early developmental multisystemic disorder. Most patients die in utero, survival beyond birth or the neonatal period is unusual. Classic disease manifestations comprise occipital meningoencephalocele, cystic kidneys, hepatobiliary ductal plate malformation and postaxial polydactyly, but additional features are common. At least 10 genes are known for MKS currently, other ciliary genes are thought to be allelic; that is why more than a dozen genes have to be considered to be disease relevant in patients with MKS. Efficient molecular genetic testing of MKS and related disorders have only become feasible with emerging next‐generation sequencing (NGS)‐based approaches. Specific disease panels (e.g. for MKS and related disorders) allow sequencing of all disease genes in parallel and very efficiently lead to reduction of turnaround times and costs.