|Title||Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly.|
|Publication Type||Journal Article|
|Year of Publication||2018|
|Authors||Di Donato, N, Timms, AE, Aldinger, KA, Mirzaa, GM, Bennett, JT, Collins, S, Olds, C, Mei, D, Chiari, S, Carvill, G, Myers, CT, Rivière, J-B, Zaki, MS, Gleeson, JG, Rump, A, Conti, V, Parrini, E, M Ross, E, Ledbetter, DH, Guerrini, R, Dobyns, WB|
|Corporate Authors||University of Washington Center for Mendelian Genomics|
|Date Published||2018 11|
|Keywords||Brain, Classical Lissencephalies and Subcortical Band Heterotopias, DNA Mutational Analysis, Female, Genetic Association Studies, Humans, Lissencephaly, Male, Mutation, Whole Exome Sequencing|
PURPOSE: To estimate diagnostic yield and genotype-phenotype correlations in a cohort of 811 patients with lissencephaly or subcortical band heterotopia.
METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.
|Alternate Journal||Genet. Med.|
|PubMed Central ID||PMC6195491|
|Grant List||R01 NS092772 / NS / NINDS NIH HHS / United States |
P01 NS039404 / NS / NINDS NIH HHS / United States
R01 NS050375 / NS / NINDS NIH HHS / United States
K08 NS092898 / NS / NINDS NIH HHS / United States
U54 HG006493 / HG / NHGRI NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
R01 NS035515 / NS / NINDS NIH HHS / United States
R01 NS058721 / NS / NINDS NIH HHS / United States