Intragenic deletions and duplications of the LIS1 and DCX genes: a major disease-causing mechanism in lissencephaly and subcortical band heterotopia

Classical lissencephaly, or isolated lissencephaly sequence (ILS), and subcortical band heterotopia (SBH) are neuronal migration disorders associated with severe mental retardation and epilepsy. Abnormalities of the LIS1 and DCX genes are implicated in the majority of patients with these disorders a...

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Bibliographic Details
Published in:	European journal of human genetics : EJHG Vol. 17; no. 7; pp. 911 - 918
Main Authors:	HAVERFIELD, Eden V, WHITED, Amanda J, PETRAS, Kristin S, DOBYNS, William B, DAS, Soma
Format:	Journal Article
Language:	English
Published:	Basingstoke Nature Publishing Group 01-07-2009
Subjects:	1-Alkyl-2-acetylglycerophosphocholine Esterase - genetics Biological and medical sciences Cell migration Classical Lissencephalies and Subcortical Band Heterotopias - genetics Clonal deletion Diagnosis DNA Mutational Analysis Doublecortin protein Epilepsy Female Fundamental and applied biological sciences. Psychology Gene Deletion Gene Duplication General aspects. Genetic counseling Genes Genetics Genetics of eukaryotes. Biological and molecular evolution Humans Leukocyte migration LIS1 protein Lissencephaly Male Malformations of the nervous system Medical genetics Medical sciences Microtubule-Associated Proteins - genetics Molecular and cellular biology Mutation Neurology Neuropeptides - genetics Severity of Illness Index Subcortical band heterotopia United States > US Chicago Illinois Chromosomal aberration Nervous system diseases Disease subcortical band heterotopia Heterotopic intragenic deletions/duplications Mechanism Cerebral disorder Gene MLPA Malformation Lissencephaly Central nervous system disease Deletion Abnormal chromosome Genetics Chromosome duplication Subcortex
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Summary:	Classical lissencephaly, or isolated lissencephaly sequence (ILS), and subcortical band heterotopia (SBH) are neuronal migration disorders associated with severe mental retardation and epilepsy. Abnormalities of the LIS1 and DCX genes are implicated in the majority of patients with these disorders and account for approximately 75% of patients with ILS, whereas mutations of DCX account for 85% of patients with SBH. The molecular basis of disease in patients with ILS and SBH, in whom no abnormalities have been identified, has been questioned. We studied a series of 83 patients with ILS, SBH or pachygyria, in whom no abnormalities of the LIS1 or DCX genes had been identified, for intragenic deletions and duplications by multiplex ligation-dependent probe amplification (MLPA). In 52 patients with ILS, we identified 12 deletions and 6 duplications involving the LIS1 gene (35%), with the majority resulting in grade 3 lissencephaly. Three deletions of the DCX gene were identified in the group of nine female patients with SBH (out of 31 patients with DCX-suggestive brain anomalies), ie 33%. We estimate an overall mutation detection rate of approximately 85% by LIS1 and DCX sequencing and MLPA in ILS, and 90% by DCX sequencing and MLPA in SBH. Our results show that intragenic deletions and duplications of the LIS1 and DCX genes account for a significant number of patients with ILS and SBH, where no molecular defect had previously been identified. Incorporation of deletion/duplication analysis of the LIS1 and DCX genes will be important for the molecular diagnosis of patients with ILS and SBH.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	1018-4813 1476-5438
DOI:	10.1038/ejhg.2008.213