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From INSERM U901 (C.C., S.K.), INMED, University de la Méditerranee, Campus de Luminy, Marseille, France; INSERM U491 (C.C., C.M.-R., E.P., L.V.), University de la Méditerranee, Faculte de Medecine La Timone, Marseille; Victorian Clinical Genetics Services (A.B., H.R.S.), Melbourne, Australia; Pediatric Neurology and Neurogenetics Unit and Laboratories (E.P., R.G.) and Medical Genetics Unit (S.G.), Children's Hospital A. Meyer-University of Florence, Italy; Departments of Medicine and Paediatrics (J.M.M., I.E.S.), The University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, Australia; Department of Laboratory Medicine (E.B.), Unit of Molecular Medicine, Bambino Gesù Hospital, Rome, Italy; Departments of Medical Genetics (C.M., A.M.) and Pediatric Neurology (B.C.), Timone Children's Hospital, Marseille, France; Genetica Medica (O.Z.), Università di Pavia, IRCCS Fondazione Policlinico San Matteo, Pavia; and Genetica Medica (F.N.), Università di Pavia, Italy.
* To whom correspondence should be addressed. E-mail: r.guerrini{at}meyer.it.
Background: Periventricular heterotopia (PH) is an etiologically heterogeneous disorder characterized by nodules of neurons ectopically placed along the lateral ventricles. Most affected patients have seizures and their cognitive level varies from normal to severely impaired. At present, two genes have been identified to cause PH when mutated. Mutations in FLNA (Xq28) and ARFGEF2 (20q13) are responsible for X-linked bilateral PH and a rare autosomal recessive form of PH with microcephaly. Chromosomal rearrangements involving the 1p36, 5p15, and 7q11 regions have also been reported in association with PH but the genes implicated remain unknown. Fourteen additional distinct anatomoclinical PH syndromes have been described, but no genetic insights into their causes have been gleaned.
Methods: We report the clinical and imaging features of three unrelated patients with epilepsy, mental retardation, and bilateral PH in the walls of the temporal horns of the lateral ventricles, associated with a de novo deletion of the 5q14.3-15 region. We used microarray-based comparative genomic hybridization to define the boundaries of the deletions.
Results: The three patients shared a common deleted region spanning 5.8 Mb and containing 14 candidate genes.
Conclusion: We identified a new syndrome featuring bilateral periventricular heterotopia (PH), mental retardation, and epilepsy, mapping to chromosome 5q14.3-q15. This observation reinforces the extreme clinical and genetic heterogeneity of PH. Array comparative genomic hybridization is a powerful diagnostic tool for characterizing causative chromosomal rearrangements of limited size, identifying potential candidate genes for, and improving genetic counseling in, malformations of cortical development.
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  C. Kubisch Chromosomal microdeletions: Minor imbalances with major consequences Neurology, March 3, 2009; 72(9): 782 - 783. [Full Text] [PDF]
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