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Meckel syndrome
1Prenatal Genetics, Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Finland.
Abstract:
Meckel syndrome (MKS) is a lethal syndrome with a central nervous system malformation, usually occipital meningoencephalocele, bilaterally large multicystic kidneys with fibrotic changes of the liver, and polydactyly in most cases. Additional anomalies are frequent. A common characteristic of the parenchymal changes of many organs is a proliferation of the stromal connective tissue and increase and dilatation of the associated epithelial ducts. Autosomal recessive inheritance is well confirmed and the gene locus has been mapped to chromosome 17q21-24 by genome wide linkage study. The locus was later refined to within a less than 1 cM region (17q22), in which most of the Finnish MKS patients share a common chromosomal haplotype suggesting one major and relatively old mutation. However, in most of the non-Finnish MKS families studied, this linkage could not be confirmed. The linkage studies provide evidence that more than one locus is involved in bringing about the combination of CNS malformations, cystic kidneys, and polydactyly, maybe even in typical cases of MKS. Prenatal diagnosis of MKS by vaginal ultrasound scan is possible from 11-12 weeks of pregnancy, especially in families where there is a known risk. In those families where linkage to 17q22 is established, prenatal diagnosis by DNA analysis is possible.
Insights
Meckel syndrome (MKS) is a rare, lethal genetic disorder characterized by severe congenital anomalies. Genetic linkage studies suggest potential genetic heterogeneity, with implications for prenatal diagnosis.
Area of Science:
- Medical Genetics
- Developmental Biology
- Clinical Genetics
Background:
- Meckel syndrome (MKS) is a lethal autosomal recessive disorder.
- Characterized by central nervous system malformations (e.g., occipital meningoencephalocele), cystic kidneys with hepatic fibrosis, and polydactyly.
- Parenchymal changes often involve stromal proliferation and ductal dilatation.
Purpose of the Study:
- To investigate the genetic basis of Meckel syndrome.
- To identify the gene locus and explore potential genetic heterogeneity.
- To establish methods for accurate prenatal diagnosis.
Main Methods:
- Genome-wide linkage studies were performed to map the MKS gene locus.
- Haplotype analysis was used to refine the locus and investigate founder mutations.
- Prenatal diagnosis was assessed using ultrasound and DNA analysis.
Main Results:
- The MKS gene locus was initially mapped to chromosome 17q21-24 and refined to 17q22.
- A common haplotype in Finnish MKS patients suggests a founder mutation.
- Linkage analysis in non-Finnish families indicated potential genetic heterogeneity, with more than one locus involved.
- Prenatal diagnosis is feasible via ultrasound from 11-12 weeks or DNA analysis if linkage is established.
Conclusions:
- Meckel syndrome exhibits genetic heterogeneity, with potential involvement of multiple loci.
- Genetic mapping and haplotype analysis are crucial for understanding MKS etiology.
- Established prenatal diagnostic methods improve early detection in at-risk families.