Abstract
Very little is known about the molecular basis of autosomal recessive MR (ARMR) because in developed countries, small family sizes preclude mapping and identification of the relevant gene defects. We therefore chose to investigate genetic causes of ARMR in large consanguineous Iranian families. This study reports on a family with six mentally retarded members. Array-based homozygosity mapping and high-resolution microarray-based comparative genomic hybridization (array CGH) revealed a deletion of approximately 150–200 kb, encompassing the promoter and the first six exons of the MCPH1 gene, one out of four genes that have been previously implicated in ARMR with microcephaly. Reexamination of affected individuals revealed a high proportion of prematurely condensed chromosomes, which is a hallmark of this condition, but in spite of the severity of the mutation, all patients showed only borderline to mild microcephaly. Therefore the phenotypic spectrum of MCPH1 mutations may be wider than previously assumed, with ARMR being the only consistent clinical finding.
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Acknowledgements
We are grateful to all family members for their cooperation, to the clinicians and health workers for the collection of samples, and to Dr. Sarah A. Shoichet for carefully reading and editing this manuscript. Thanks are also due to Dr. P. de Jong at the BACPAC Resources Center (CHORI 2005), the COST B19 Action “Molecular Cytogenetics of Solid Tumors”, and to the Mapping Core and Map Finishing groups of the Wellcome Trust Sanger Institute for the supply of clones and for clone verification. This work was supported by the Max Planck Innovation Fund. Chip mapping and the development of CGH arrays was supported by the German National Genome Research Network, grant no. 01GR0104 to PN and grant no. 01GR0203 to HHR, respectively.
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Garshasbi, M., Motazacker, M.M., Kahrizi, K. et al. SNP array-based homozygosity mapping reveals MCPH1 deletion in family with autosomal recessive mental retardation and mild microcephaly. Hum Genet 118, 708–715 (2006). https://doi.org/10.1007/s00439-005-0104-y
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DOI: https://doi.org/10.1007/s00439-005-0104-y