Molecular diagnostics of Meckel–Gruber syndrome highlights phenotypic differences between MKS1 and MKS3
- 22 March 2007
- journal article
- Published by Springer Science and Business Media LLC in Human Genetics
- Vol. 121 (5), 591-599
- https://doi.org/10.1007/s00439-007-0341-3
Abstract
Meckel–Gruber syndrome (MKS) is a recessively inherited, lethal disorder characterized by renal cystic dysplasia, occipital encephalocele, polydactyly and biliary dysgenesis. MKS is genetically heterogeneous with three loci mapped and two identified; MKS1 (17q23) and MKS3 (8q22.1). MKS1 is part of the Finnish disease heritage, while MKS3 has been described exclusively in consanguineous Asian families. Here we aimed to establish molecular diagnostics for MKS, determine the importance of MKS1 and MKS3 in non-consanguineous populations, and study genotype/phenotype correlations. The coding regions of MKS1 and MKS3 were screened for mutations by direct sequencing in 17 families clinically diagnosed with MKS in the US or The Netherlands. The clinical phenotype was compared to genic and allelic effects. Both mutations were identified in ten families; five MKS1 and five MKS3. All but two were compound heterozygotes, consistent with their non-consanguineous nature. The MKS1-Finmajor mutation accounted for 7/10 MKS1 mutations; two novel changes were additionally detected. Seven novel mutations were found in MKS3, including three missense changes. We concluded that MKS1 and MKS3 account for the majority of MKS in non-consanguineous populations of European origin. Polydactyly is usually found in MKS1 but rare in MKS3. Cases with no, or milder, CNS phenotypes were only found in MKS3; hypomorphic missense mutations may be associated with less severe CNS outcomes. This study is consistent with further genetic heterogeneity of MKS, but underlines the value of molecular diagnostics of the known genes to aid family planning decisions.Keywords
This publication has 32 references indexed in Scilit:
- The Meckel-Gruber Syndrome Gene, MKS3, Is Mutated in Joubert SyndromeAmerican Journal of Human Genetics, 2007
- MKS1, encoding a component of the flagellar apparatus basal body proteome, is mutated in Meckel syndromeNature Genetics, 2006
- The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk ratNature Genetics, 2006
- Prenatal Diagnosis of the Meckel-Gruber Syndrome from 11th to 20th Gestational WeekUltraschall in der Medizin - European Journal of Ultrasound, 2004
- A novel locus for Meckel-Gruber syndrome, MKS3 , maps to chromosome 8q24Human Genetics, 2002
- A Gene for Meckel Syndrome Maps to Chromosome 11q13American Journal of Human Genetics, 1998
- Meckel syndrome.Journal of Medical Genetics, 1998
- Improved Splice Site Detection in GenieJournal of Computational Biology, 1997
- The locus for Meckel syndrome with multiple congenital anomalies maps to chromosome 17q21–q24Nature Genetics, 1995
- The Cardinal Manifestations of Bardet–Biedl Syndrome, a Form of Laurence–Moon–Biedl SyndromeNew England Journal of Medicine, 1989