TY - JOUR
T1 - Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly
AU - University of Washington Center for Mendelian Genomics
AU - Di Donato, Nataliya
AU - Timms, Andrew E.
AU - Aldinger, Kimberly A.
AU - Mirzaa, Ghayda M.
AU - Bennett, James T.
AU - Collins, Sarah
AU - Olds, Carissa
AU - Mei, Davide
AU - Chiari, Sara
AU - Carvill, Gemma
AU - Myers, Candace T.
AU - Rivière, Jean Baptiste
AU - Zaki, Maha S.
AU - Gleeson, Joseph G.
AU - Rump, Andreas
AU - Conti, Valerio
AU - Parrini, Elena
AU - Ross, M. Elizabeth
AU - Ledbetter, David H.
AU - Guerrini, Renzo
AU - Dobyns, William B.
N1 - Publisher Copyright:
© 2018, American College of Medical Genetics and Genomics.
PY - 2018/11/1
Y1 - 2018/11/1
N2 - 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.
AB - 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.
KW - actinopathy
KW - lissencephaly
KW - reelinopathy
KW - subcortical band heterotopia
KW - tubulinopathy
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U2 - 10.1038/gim.2018.8
DO - 10.1038/gim.2018.8
M3 - Article
C2 - 29671837
AN - SCOPUS:85052475110
SN - 1098-3600
VL - 20
SP - 1354
EP - 1364
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 11
ER -