1.1 Name of the disease (synonyms)
1.2 OMIM# of the disease
Type 1 MIM #249000, type 2 MIM #603194, type 3 MIM #607361, type 4 MIM #611134, type 5 MIM #611561, and type 6 MIM #612284.
1.3 Name of the analysed genes or DNA/chromosome segments
1.4 OMIM# of the gene(s)
MKS1, MIM# 609883; TMEM216, MIM# 613277; TMEM67, MIM# 609884; CEP290, MIM# 610142; RPGRIP1L, MIM# 610937; and CC2D2A MIM# 612013.
1.5 Mutational spectrum
Data according to published literature and the HGMD database (release date 24 September 2010; https://portal.biobase-international.com)
MKS1: Major mutation c.1408-7_35del p.Gly470fs. In addition, 17 other mutations listed so far for patients with the Meckel–Gruber phenotype (three nonsense, one missense, seven canonical splice-site mutations, four small deletions/duplications, one silent mutation, and one intronic 143-bp deletion, both leading to aberrant splicing).3, 12, 13
TMEM216/MKS2: Three different mutations described so far in patients with Meckel–Gruber syndrome (one nonsense, one splicing, and one missense mutation).6
TMEM67/MKS3: Wide mutational spectrum without significant hotspot mutation in non-isolated cohorts. So far, 37 different mutations described in patients with the Meckel–Gruber phenotype (5 nonsense, 17 missense, 7 canonical splice-site mutations, 7 small deletions/insertions/duplications, and 1 gross deletion described at genomic DNA level encompassing exons 17–21).3, 13, 14
CEP290/MKS4: Recurrent mutation c.1219_1220del p.Met407fs in several families. A total of 13 different mutations described so far in patients with the Meckel–Gruber phenotype (five nonsense, two canonical splice-site mutations, and six small deletions/insertions/duplications).8, 9
RPGRIP1L/MKS5: Only four different mutations in MKS cases described so far (three nonsense and one missense mutation).
CC2D2A/MKS6: Major mutation c.1762C>T p.Val587fs. In addition, 17 mainly family-specific mutations identified in patients with MKS (four nonsense, one missense, six splice-site mutations, five small deletions/insertions, and one gross deletion described at genomic DNA level encompassing exons 28–31).11, 15
Currently, it is still hard to give exact figures on the contribution of each of the above genes to the total mutational load in Meckel–Gruber syndrome. There will be further genetic heterogeneity. However, MKS1, MKS3/TMEM67, and MKS6/CC2D2A might be major MKS genes, followed by MKS4/CEP290.3, 11, 15, 16 Currently, the role of MKS2/TMEM216 in Meckel–Gruber syndrome can only be speculated upon, whereas MKS5/RPGRIP1L seems to be quite rarely mutated in typical cases of Meckel syndrome.
Mutations in all MKS genes are mainly truncating, whereas in MKS3 missense mutations are also frequent.
1.6 Analytical methods
Consanguineous and multiplex pedigrees were assessed using initial linkage analysis of known loci with subsequent sequencing in case of compatible haplotypes.
Mainly sequencing was carried out in sporadic cases originating from non-consanguineous marriages because of family-specific mutations in most cases.
1.7 Analytical validation
Most of the mutations have been identified on research basis by sequencing using a protocol that is validated in most laboratories.
1.8 Estimated frequency of the disease (incidence at birth (‘birth prevalence') or population prevalence)
1.9 If applicable, prevalence in the ethnic group of the investigated person:
In Finland and other isolated and/or consanguineous cohorts, the prevalence was much more frequent (most probably >1/5000–10000).
1.10 Diagnostic setting:
Comment: If the causative gene and mutation of MKS can be identified, carrier screening of the relatives becomes possible as well as molecular prenatal diagnosis and preimplantation diagnosis.