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Autosomal recessive mental retardation: homozygosity mapping identifies 27 single linkage intervals, at least 14 novel loci and several mutation hotspots

Abstract

Mental retardation (MR) has a worldwide prevalence of around 2% and is a frequent cause of severe disability. Significant excess of MR in the progeny of consanguineous matings as well as functional considerations suggest that autosomal recessive forms of MR (ARMR) must be relatively common. To shed more light on the causes of autosomal recessive MR (ARMR), we have set out in 2003 to perform systematic clinical studies and autozygosity mapping in large consanguineous Iranian families with non-syndromic ARMR (NS-ARMR). As previously reported (Najmabadi et al. in Hum Genet 121:43–48, 2007), this led us to the identification of 12 novel ARMR loci, 8 of which had a significant LOD score (OMIM: MRT5–12). In the meantime, we and others have found causative gene defects in two of these intervals. Moreover, as reported here, tripling the size of our cohort has enabled us to identify 27 additional unrelated families with NS-ARMR and single-linkage intervals; 14 of these define novel loci for non-syndromic ARMR. Altogether, 13 out of 39 single linkage intervals observed in our cohort were found to cluster at 6 different loci on chromosomes, i.e., 1p34, 4q27, 5p15, 9q34, 11p11–q13 and 19q13, respectively. Five of these clusters consist of two significantly overlapping linkage intervals, and on chr 1p34, three single linkage intervals coincide, including the previously described MRT12 locus. The probability for this distribution to be due to chance is only 1.14 × 10−5, as shown by Monte Carlo simulation. Thus, in contrast to our previous conclusions, these novel data indicate that common molecular causes of NS-ARMR do exist, and in the Iranian population, the most frequent ones may well account for several percent of the patients. These findings will be instrumental in the identification of the underlying genes.

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Acknowledgments

We are grateful to all affected individuals and their families for their participation in the study. We would like to have special thanks to Dr. Shahrbanoo Nakhai, the head of USWR for financial support. This work was supported by the Max Planck Innovation Fund and a grant form the German Federal Ministry of Education and Research to H.H.R. (MRNET 01GS08161-2) and D.W. (MRNET 01GS08167). H.N., H.H.R., A.W.K., K.K. and A.T. are members of the GENCODYS consortium. This work was also supported financially by a grant from the Iranian National Science Foundation.

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Correspondence to Hans Hilger Ropers or Hossein Najmabadi.

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A. W. Kuss, M. Garshasbi contributed equally.

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Kuss, A.W., Garshasbi, M., Kahrizi, K. et al. Autosomal recessive mental retardation: homozygosity mapping identifies 27 single linkage intervals, at least 14 novel loci and several mutation hotspots. Hum Genet 129, 141–148 (2011). https://doi.org/10.1007/s00439-010-0907-3

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Keywords

  • Mental Retardation
  • Gene Defect
  • Consanguineous Family
  • Homozygosity Mapping
  • Respective Family