Genotype-phenotype correlations at the MKS1 and MKS3 loci in Meckel syndrome and related phenotypes. R. KHADDOUR¹, L. BAALA¹, U.M. SMITH², C. OZILOU¹, J. MARTINOVIC¹, S. AUDOLLENT¹, C. ESCULPAVIT¹, N. KADHOM¹, M. KYTALLA³, A. MUNNICH¹, F. RAZAVI¹, E. GENIN⁴, J. ROUME⁵, M.C. GUBLER⁶, M. VEKEMANS¹, C.A. JOHNSON², T. ATTIE-BITACH¹. 1) Genetics and INSERM U781, Hopital Necker, Paris, France; 2) Medical and Molecular Genetics, University of Birmingham Medical School, Birmingham; 3) Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland; 4) INSERM U535, Hôpital Paul Brousse, Villejuif; 5) Génétique Médicale, CHI Poissy, Saint Germain en Laye; 6) INSERM U574, Hopital Necker, Paris.
   Meckel syndrome (MKS) is a lethal autosomal recessive disease characterized by cystic kidneys, a brain malformation (usually occipital encephalocele), polydactyly, and hepatic developmental defects. Recently, two genes have been identified: MKS1 on 17q in Finnish kindreds and MKS3 on 8q in families from Pakistan and Oman, encoding ciliary proteins. We report on the sequence analysis of the MKS1 and MKS3 genes in a large multhiethnic cohort of 56 cases of MKS as defined by Salonen and 45 related phenotype or Meckel-like. MKS1 recessive mutations were identified in 6 families with classical MKS phenotype. Most mutations abolished the B9 conserved domain of the protein. One case had a situs inversus. Two cases, from families of French origin, carried the Finnish major mutation allowing us to estimate its age to 4350 years. Seven fetuses carried MKS3 mutations or a large intragenic deletion. All missense mutations lied in the extracellular domain of the protein. Polydactyly was significantly less frequent when carrying MKS3 (2/12) than MKS1 mutations (8/10). All had bile duct proliferation of liver. In contrast to MKS1, brain phenotype varied from occipital encephalocele, isolated Dandy-Walker malformation to normal brain in one case. Two sibs presented vermis agenesis and small cysts in renal medulla, a phenotype not usually observed in MKS. Our results indicate that MKS1 and MKS3 genes are each responsible for at least 10 % of MKS cases with various mutations in different populations. A strong phenotype/genotype correlation was observed concerning the polydactyly, brain and kidney anomalies.