To estimate diagnostic yield and genotype-phenotype correlations in a cohort of 811 patients with lissencephaly or subcortical band heterotopia.
We collected DNA from 756 children with lissencephaly over 30 years. Many were tested for deletion 17p13.3 and mutations of LIS1, DCX, and ARX, but few other genes. Among those tested, 216 remained unsolved and were tested by a targeted panel of 17 genes (ACTB, ACTG1, ARX, CRADD, DCX, LIS1, TUBA1A, TUBA8, TUBB2B, TUBB, TUBB3, TUBG1, KIF2A, KIF5C, DYNC1H1, RELN, and VLDLR) or by whole-exome sequencing. Fifty-five patients studied at another institution were added as a validation cohort.
The overall mutation frequency in the entire cohort was 81%. LIS1 accounted for 40% of patients, followed by DCX (23%), TUBA1A (5%), and DYNC1H1 (3%). Other genes accounted for 1% or less of patients. Nineteen percent remained unsolved, which suggests that several additional genes remain to be discovered. The majority of unsolved patients had posterior pachygyria, subcortical band heterotopia, or mild frontal pachygyria.
The brain-imaging pattern correlates with mutations in single lissencephaly-associated genes, as well as in biological pathways. We propose the first LIS classification system based on the underlying molecular mechanisms.
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Research reported in this publication was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation, to N.D.D.); the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under awards P01NS039404, R01NS050375, 1R01NS058721, 1R01NS092772 (to W.B.D.), R01NS35515 (to M.E.R. and W.B.D.), and K08NS092898 (to G.M.M.); the National Institute of Child Health and Human Development under award R01HD20619 (to D.H.L.); and the EU Seventh Framework Program under project DESIRE grant agreements N602531 and E-RareJTC2011 (to R.G.). Exome sequencing in this study was partly provided by the University of Washington Center for Mendelian Genomics and was funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute through grant U54HG006493 (to Debbie Nickerson, Jay Shendure, and Michael Bamshad) who are the part of the UW Center for Mendelian Genomics. We thank the many patients and their families, as well as the physicians and genetic counselors who referred them,, for their important contributions to this research over more than 30 years. The content is solely the responsibility of the authors, and does not necessarily represent the official views of the National Institutes of Health. The funding sources had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data, preparation, review, or approval of the manuscript, or decision to submit the manuscript for publication.
The authors declare no conflict of interest.
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