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Spectrum of MKS1 and MKS3 mutations in Meckel syndrome: a genotype-phenotype correlation

✍ Scribed by Rana Khaddour; Ursula Smith; Lekbir Baala; Jéléna Martinovic; Davina Clavering; Rizwana Shaffiq; Catherine Ozilou; Andrew Cullinane; Mira Kyttälä; Stavit Shalev; Sophie Audollent; Camille d'Humières; Noman Kadhom; Chantal Esculpavit; Géraldine Viot; Claire Boone; Christine Oien; Férechté Encha-Razavi; Philip A Batman; Christopher P Bennett; C Geoffrey Woods; Joelle Roume; Stanislas Lyonnet; Emmanuelle Génin; Martine Le Merrer; Arnold Munnich; Marie-Claire Gubler; Phillip Cox; Fiona Macdonald; Michel Vekemans; Colin A. Johnson; Tania Attié-Bitach

Publisher
John Wiley and Sons
Year
2007
Tongue
English
Weight
367 KB
Volume
28
Category
Article
ISSN
1059-7794

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✦ Synopsis

Meckel syndrome (MKS) is a rare autosomal recessive lethal condition characterized by central nervous system malformations (typically occipital meningoencephalocele), postaxial polydactyly, multicystic kidney dysplasia, and ductal proliferation in the portal area of the liver. MKS is genetically heterogeneous and three loci have been mapped respectively on 17q23 (MKS1), 11q13 (MKS2), and 8q24 (MKS3). Very recently, two genes have been identified: MKS1/FLJ20345 on 17q in Finnish kindreds, carrying the same intronic deletion, c.1408-35_c.1408-7del29, and MKS3/TMEM67 on 8q in families from Pakistan and Oman. Here we report the genotyping of the MKS1 and MKS3 genes in a large, multiethnic cohort of 120 independent cases of MKS. Our first results indicate that the MKS1 and MKS3 genes are each responsible for about 7% of MKS cases with various mutations in different populations. A strong phenotype-genotype correlation, depending on the mutated gene, was observed regarding the type of central nervous system malformation, the frequency of polydactyly, bone dysplasia, and situs inversus. The MKS1 c.1408-35_1408-7del29 intronic mutation was identified in three cases from French or English origin and dated back to 162 generations (approx. 4050 years) ago. We also identified a common MKS3 splice-site mutation, c.1575+1G>A, in five Pakistani sibships of three unrelated families of Mirpuri origin, with an estimated age-of-mutation of 5 generations (125 years).

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