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Multiplex ligation-dependent probe amplification detects DCX gene deletions in band heterotopia

From the Research Institute I.R.C.C.S. Stella Maris Foundation, Italy (C.M.); Pediatric Neurology Unit and Laboratories, Children’s Hospital A. Meyer-University of Florence, Italy (D.M., E.P., R.G.); Departments of Child Neurology and Psychiatry (R.G.) and Biology, Developmental and Cellular Biology Unit (M.P., S.M.), University of Pisa, Italy; Department of Child Neurology and Psychiatry, University of Messina, Italy (G.T.); Department of Child Neurology and Psychiatry, University of Bologna and S. Orsola-Malpighi Hospital, Italy (E.F.); and Medical Genetic Laboratory, "Ospedali Riuniti" Bergamo, Italy (U.G.).

Address correspondence and reprint requests to Dr. Renzo Guerrini, Pediatric Neurology Unit and Laboratories, Children’s Hospital A. Meyer-University of Florence, via Luca Giordano 13, 50123, Florence, Italy; e-mail: r.guerrini{at}mcyer.it

Background: Subcortical band heterotopia (SBH, or double cortex syndrome) is a neuronal migration disorder consisting of heterotopic bands of gray matter located between the cortex and the ventricular surface, with or without concomitant pachygyria. Most cases show diffuse or anteriorly predominant (A>P) migration abnormality. All familial and 53% to 84% of sporadic cases with diffuse or A>P SBH harbor a mutation of the DCX gene, leaving the genetic causes unexplained, and genetic counseling problematic, in the remaining patients. Our purpose was to verify the extent to which exonic deletions or duplications of the DCX gene would account for sporadic SBH with A>P gradient but normal gene sequencing.

Methods: We identified 23 patients (22 women, 1 man) with sporadic, diffuse, or anteriorly predominant SBH. After sequencing the DCX gene and finding mutations in 12 (11 women, 1 man), we used multiplex ligation-dependent probe amplification (MLPA) to search for whole-exon deletions or duplications in the 11 remaining women. We used semiquantitative fluorescent multiplex PCR (SQF-PCR) and Southern blot to confirm MLPA findings.

Results: MLPA assay uncovered two deletions encompassing exons 3 to 5, and one involving exon 6, in 3 of 11 women (27%) and raised the percentage of DCX mutations from 52% to 65% in our series. SQF-PCR performed in all three women and Southern blot analysis performed in two confirmed the deletions.

Conclusions: MLPA uncovers large genomic deletions of the DCX gene in a subset of patients with SBH in whom no mutations are found after gene sequencing. Deletions of DCX are an underascertained cause of SBH.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the February 6 issue to find the title link for this article.

Disclosure: The authors report no conflicts of interest.

Received April 19, 2006. Accepted in final form October 19, 2006.

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Neurology 2007 68: 397. [Full Text] [PDF]