Article

Identification of a novel recessive RELN mutation using a homozygous balanced reciprocal translocation

Cornell University, Итак, New York, United States
American Journal of Medical Genetics Part A (Impact Factor: 2.05). 05/2007; 143A(9):939-44. DOI: 10.1002/ajmg.a.31667
Source: PubMed

ABSTRACT Two siblings from a consanguineous Egyptian marriage showed an identical phenotype of cortical lissencephaly with cerebellar hypoplasia, severe epilepsy, and mental retardation. Examination of karyotype revealed 46, t(7;12)(q22;p13)mat (7;12)(q22;p13)pat in both affected children, suggesting a homozygous reciprocal balanced translocation. Each healthy parent was a carrier of the balanced translocation in the heterozygous state, suggesting homozygous disruption of a gene involved in brain development. There were early spontaneous abortions in this family, as would be expected from transmission of an unbalanced chromosome. A disruption of RELN at 7q22.1 with absence of encoded protein was identified. This is the first demonstration that such rare homozygous translocations can be used to identify recessive disease gene mutations.

Full-text

Available from: Joseph Gleeson, Dec 18, 2013
2 Followers
 · 
98 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Malformations of cortical development are common causes of developmental delay and epilepsy. Some patients have early, severe neurological impairment, but others have epilepsy or unexpected deficits that are detectable only by screening. The rapid evolution of molecular biology, genetics, and imaging has resulted in a substantial increase in knowledge about the development of the cerebral cortex and the number and types of malformations reported. Genetic studies have identified several genes that might disrupt each of the main stages of cell proliferation and specification, neuronal migration, and late cortical organisation. Many of these malformations are caused by de-novo dominant or X-linked mutations occurring in sporadic cases. Genetic testing needs accurate assessment of imaging features, and familial distribution, if any, and can be straightforward in some disorders but requires a complex diagnostic algorithm in others. Because of substantial genotypic and phenotypic heterogeneity for most of these genes, a comprehensive analysis of clinical, imaging, and genetic data is needed to properly define these disorders. Exome sequencing and high-field MRI are rapidly modifying the classification of these disorders.
    The Lancet Neurology 06/2014; DOI:10.1016/S1474-4422(14)70040-7 · 21.82 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The role of Reelin during cerebral cortical neuron migration has long been studied, but the Reelin signaling pathway and its possible interactions are just beginning to be unraveled. Reelin is not only important in cerebral cortical migration, but has recently been shown to interact with the Notch signaling pathway and to be critical for radial glial cell number and morphology. Lee and Song (2013) show a new Notch- and Reelin-dependent role for radial glia in the mouse spinal cord: to act as a fine filter that allows somatic motor neuron axons but not cell bodies to traverse out of the CNS. Here, the types of neuronal migration are discussed, focusing on motor neurons and cues for proper localization. The interaction of Reelin signaling with the Notch pathway is reviewed, which dictates the proper formation of radial glia in the spinal cord in order to prevent ectopic motor neuron migration (Lee and Song, 2013). Future studies may reveal novel interactions and further insights as to how Reelin functions throughout the developing nervous system.
    Experimental Neurology 03/2014; DOI:10.1016/j.expneurol.2014.02.024 · 4.62 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective To establish the genetic basis of Landau-Kleffner syndrome (LKS) in a cohort of two discordant monozygotic (MZ) twin pairs and 11 isolated cases.Methods We used a multifaceted approach to identify genetic risk factors for LKS. Array comparative genomic hybridization (CGH) was performed using the Agilent 180K array. Whole genome methylation profiling was undertaken in the two discordant twin pairs, three isolated LKS cases, and 12 control samples using the Illumina 27K array. Exome sequencing was undertaken in 13 patients with LKS including two sets of discordant MZ twins. Data were analyzed with respect to novel and rare variants, overlapping genes, variants in reported epilepsy genes, and pathway enrichment.ResultsA variant (cG1553A) was found in a single patient in the GRIN2A gene, causing an arginine to histidine change at site 518, a predicted glutamate binding site. Following copy number variation (CNV), methylation, and exome sequencing analysis, no single candidate gene was identified to cause LKS in the remaining cohort. However, a number of interesting additional candidate variants were identified including variants in RELN, BSN, EPHB2, and NID2.SignificanceA single mutation was identified in the GRIN2A gene. This study has identified a number of additional candidate genes including RELN, BSN, EPHB2, and NID2.A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
    Epilepsia 05/2014; 55(6). DOI:10.1111/epi.12645 · 4.58 Impact Factor