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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.
MKS1, MIM# 609883; TMEM216, MIM# 613277; TMEM67, MIM# 609884; CEP290, MIM# 610142; RPGRIP1L, MIM# 610937; and CC2D2A MIM# 612013.
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.
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.
Most of the mutations have been identified on research basis by sequencing using a protocol that is validated in most laboratories.
In Finland and other isolated and/or consanguineous cohorts, the prevalence was much more frequent (most probably >1/5000–10000).
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.
(proportion of positive tests if the genotype is present)
(proportion of negative tests if the genotype is not present)
(proportion of positive tests if the disease is present)
Clinical sensitivity can be dependent on variable factors, such as age or family history. In such cases a general statement should be given, even if a quantification can only be made case by case.
Clinical sensitivity is not known so far. Currently, six genes with a number of mutations have been identified as the causes of Meckel syndrome. There is a big variation in the distribution of these mutations in different populations, and some additional genes are still to be identified.6, 16, 17
(proportion of negative tests if the disease is not present)
Clinical specificity can be dependent on variable factors, such as age or family history. In such cases a general statement should be given, even if a quantification can only be made case by case.
(lifetime risk to develop the disease if the test is positive)
(probability not to develop the disease if the test is negative)
Assume an increased risk based on family history for a non-affected person. Allelic and locus heterogeneity may need to be considered.
Index case in that family had been tested:
Index case in that family had not been tested:
(To be answered if in 1.10 ‘A' was marked)
The condition is lethal.
(To be answered if in 1.10 ‘B' was marked)
Early prenatal diagnostics and preimplantation diagnosis become possible.
Prenatal diagnosis by ultrasound scan and termination of pregnancy in case of an affected fetus.
(To be answered if in 1.10 ‘C' was marked)
Yes, in genetic counselling carrier testing of family members becomes possible.
(To be answered if in 1.10 ‘D' was marked)
Early genetic testing from chorionic villi is possible. Ultrasound scan detects the multicystic kidneys and malformations of the head, brain, and extremities.
Please assume that the result of a genetic test has no immediate medical consequences. Is there any evidence that a genetic test is nevertheless useful for the patient or his/her relatives? (Please describe)
Preimplantation diagnosis becomes possible.
This work was supported by EuroGentest, an EU-FP6 supported NoE, contract number 512148 (EuroGentest Unit 3: ‘Clinical genetics, community genetics and public health', Workpackage 3.2).
The authors declare no conflict of interest.