Type of disorder: genic/chromosomal
Cause: genetically heterogeneous
Inheritance: autosomal recessive
Required testing: sequencing, large deletion/duplication testing (qPCR/MLPA), possibly FISH/CGH array.
Alterantive testing: exome sequencing
Meckel syndrome (or Meckel-Gruber syndrome) is a complex malformation disorder showing autosomal recessive inheritance. The outcome is lethal, with death occurring mostly in the perinatal period. Meckel–Gruber syndrome is classified as a ciliopathy and may show clinical and genetic overlap with other ciliopathies like Joubert syndrome (to date, 24 genes have been found mutated in Joubert syndrome, of which 13 also cause Meckel syndrome). Other known ciliopathies include primary ciliary dyskinesia, Bardet–Biedl syndrome, polycystic kidney, nephronophthisis, Alstrom syndrome, and some forms of retinal degeneration.
Enlarged kidneys with numerous fluid-filled cysts are a distinctive feature of Meckel syndrome and are often found together with occipital encephalocele and polydactyly. Most patients also show liver fibrosis.
Meckel syndrome prevalence changes across different geographical regions, varying from 1 in 13,000 to 1 in 140,000 people. It is more common in certain populations, like, for example, the Finnish (1 in 9,000 people) or the Belgian (1 in 3,000 people).
Prenatal diagnosis is often possible by ultrasound examination, by finding an intracranial cystic image and/or a skull defect at the end of the first trimester, as well as the main feature consistent: abnormally enlarged kidneys. Other malformations may be detected at more advanced stages of pregnancy. Elevated amniotic alpha-fetoprotein (due to encephalocele) might be detected by the amniocentesis.
Meckel syndrome is a genetically heterogeneous disorder. To date pathogenic mutations have been detected to occur in one of the following genes (but mutations in additional genes may be discovered in future): MKS1, TMEM216, TMEM67, CEP290, RPGRIP1L, CC2D2A, NPHP3, TCTN2, B9D1, B9D2, TMEM231, and KIF14. Few data are available on the mutations detection rate when analysing the aforementioned genes, therefore exome sequencing may be considered as an alternative for the genetic testing of patients with a clinically confirmed diagnosis of Meckel syndrome. Mutations identified include point mutations and microdeletions. Point mutations may be detected by sequencing, but chromosomal microdeletions require special techniques like qPCR or MLPA or a cytogenetic approach by FISH or CGH array (because homozygosity at sequencing might hide what's actually a hemizygosis).
