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Deep sequencing reveals 50 novel genes for recessive cognitive disorders

Abstract

Common diseases are often complex because they are genetically heterogeneous, with many different genetic defects giving rise to clinically indistinguishable phenotypes. This has been amply documented for early-onset cognitive impairment, or intellectual disability, one of the most complex disorders known and a very important health care problem worldwide. More than 90 different gene defects have been identified for X-chromosome-linked intellectual disability alone, but research into the more frequent autosomal forms of intellectual disability is still in its infancy. To expedite the molecular elucidation of autosomal-recessive intellectual disability, we have now performed homozygosity mapping, exon enrichment and next-generation sequencing in 136 consanguineous families with autosomal-recessive intellectual disability from Iran and elsewhere. This study, the largest published so far, has revealed additional mutations in 23 genes previously implicated in intellectual disability or related neurological disorders, as well as single, probably disease-causing variants in 50 novel candidate genes. Proteins encoded by several of these genes interact directly with products of known intellectual disability genes, and many are involved in fundamental cellular processes such as transcription and translation, cell-cycle control, energy metabolism and fatty-acid synthesis, which seem to be pivotal for normal brain development and function.

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Figure 1: Known and novel intellectual disability genes form protein and regulatory networks.

Accession codes

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Sequence Read Archive

Data deposits

Raw sequencing data can be retrieved from the Sequence Read Archive (SRA), accession number SRA036250.

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Acknowledgements

We express our gratitude to the patients and their families for their participation in the study. We thank S. Nakhee and K. Javan for their support; S. Arzhangi, S. Banihashemi, M. Kasiri, H. Khodaee, M. Schlicht and M. Gerloff for contributing to this project in various ways; G. Eder for her assistance with the preparation of the manuscript; and S. Shoichet for critically reading the manuscript. This work was supported by the Max Planck Innovation Funds, the German Federal Ministry of Education and Research through the MRNET (grant 01GS08161, to H.H.R.), the Iranian National Science Foundation and the EU-FP7 project GENCODYS.

Author information

Authors and Affiliations

Authors

Contributions

H.H.R. and H.N. initiated and directed this study. H.H., M.G., W.C., S.H., K.W., V.K., R.U., K.K. and A.W.K. contributed to its design and coordination. H.N., K.K., A.T., P.J., V.H., D.W., M.C., I.R., F.M., C.H., A.D., A.R., M.J.S.B., M.F. and H.D. recruited patients and families, and K.K. and A.T. were responsible for the clinical investigations. F.B., S.G.F. and R.K. did the karyotyping. M.G. performed the linkage analyses and together with R.W. and H.H., he established data management tools. R.U. and I.M. performed exon enrichments, and C.J. and M.B. did the deep sequencing experiments. H.H. analysed the sequencing data and provided bioinformatics support. M.G., S.S.A., M.H., A.Z., M.M., L.P., L.N.V., L.A.M., F.L., B.L., S.E.-N., Z.F., J.H., L.M. and A.W.K. participated in the validation of the results and the segregation analyses. T.Z. performed the pathway analyses. H.H., M.G., A.Z., L.P., R.W., T.Z., L.M., A.W.K., A.T., K.K., H.N. and H.H.R. evaluated and interpreted the results, and H.H.R., H.H. and M.G. wrote the manuscript.

Corresponding authors

Correspondence to Kimia Kahrizi or H. Hilger Ropers.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Methods, Supplementary Figures 1-2 with legends and additional references. (PDF 264 kb)

Supplementary Table 1

The table shows families information. (XLS 138 kb)

Supplementary Table 2

The table shows mutations information. (XLS 83 kb)

Supplementary Table 3

The table shows population specific control screening in novel (candidate) genes for ID. (XLS 25 kb)

Supplementary Table 4

The table shows a list of truncating mutations that did not co-segregate with ID. (XLS 17 kb)

Supplementary Table 5

The table shows table coverage for 136 ARMR samples in the targeted exons. (XLS 18 kb)

Supplementary Table 6

The table shows homozygous variants detected by SNP array and NGS in the targeted exons. (XLS 16 kb)

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Najmabadi, H., Hu, H., Garshasbi, M. et al. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478, 57–63 (2011). https://doi.org/10.1038/nature10423

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