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Mixed Message: 15q13.3 Deletions Confer Risk, But for What?

19 January 2009. A new study led by the EPICURE Integrated Project, a European research consortium devoted to unraveling the genomics and neurobiology of epilepsy, has linked microdeletions in 15q13.3 with idiopathic generalized epilepsies (IGEs), seizure disorders that comprise up to one-third of all epilepsy cases.

Deletions in the same region have recently been associated with schizophrenia (see SRF related news story), but deletion carriers identified in the EPICURE study have no history of psychosis, and the deletion was also seen in unaffected relatives of probands with epilepsy. The wide phenotypic range reported in these studies mirrors that seen in other analyses of copy-number variations (CNVs) and presents a challenge to the common disease/common variant hypothesis that has guided most genomic research to date (see SRF related news story and Q&A with Evan Eichler and Heather Mefford [also authors on the EPICURE paper] regarding their work on CNVs in 1q21.1). The study appears in the January 11 online edition of Nature Genetics, with Thomas Sander of the University of Cologne, Germany, as corresponding author.

The 15q13–q14 region had previously been implicated in epilepsy in linkage studies (Neubauer et al., 1998; Elmslie et al., 1997; Sander et al., 2000) that proposed a pathogenic role for mutations in the CHRNA4 and CHRNA7 genes in this region, which code for the α4 and α7 subunits of the nicotinic acetylcholine receptor (see SRF related news story for a review of current thinking on cholinergic receptors and schizophrenia). More recently, Andrew Sharp, Mefford, Eichler, and colleagues at the University of Washington associated a 1.5 Mb microdeletion in the 15q13.3 region, which includes CHRNA7 and six other genes, with a syndrome characterized by mental retardation and seizures (Sharp et al., 2008).

In the new study, first author Ingo Helbig and the EPICURE team looked for the same 1.5 Mb deletion in DNA samples from 1,223 individuals with IGE and 3,699 ancestrally matched controls, and found the deletion in 12 (1 percent) of the IGE cases (including one case with an overlapping 3.8 mb deletion) but in none of the controls. The prevalence of this structural variant in the general population has been estimated at 0.02 percent, so the EPICURE study suggests that the deletion is 50 times more common in those with IGE.

However, as in earlier CNV studies, this clear conclusion is muddied by the mixed clinical picture of the probands’ relatives. In one case, the 15q13.3 deletion was de novo. In four other cases for which parental DNA was available, the deletion was inherited, yet no seizure disorders were reported in the affected parents. Three siblings who carried the deletion suffered from IGE, and a fourth had severe intellectual disability with no history of seizures. Moreover, as noted above, no psychosis was reported in any proband, and most showed none of the other phenotypes that have also been associated with the 15q13.3 deletion, which include mental retardation, autism, growth retardation, and dysmorphic features.

Surveying the recent literature, the authors write, “Taken together, the current studies reveal extensive variability in the phenotypic manifestation associated with the 15q13.3 deletion, ranging from apparently healthy individuals to severely affected individuals with a broad spectrum of neuropsychiatric disorders.... These findings...argue for a new framework for understanding complex genetic diseases.”—Pete Farley.

Reference:
Helbig I, Mefford HC, Sharp AJ, Guipponi M, Fichera M, Franke A, Muhle H, de Kovel C, Baker C, von Spiczak S, Kron KL, Steinich I, Kleefuß-Lie AA, Leu C, Gaus V, Schmitz B, Klein KM, Reif PS, Rosenow F, Weber Y, Lerche H, Zimprich F, Urak L, Fuchs K, Feucht M, Genton P, Thomas P, Visscher F, de Haan GJ, Møller RS, Hjalgrim H, Luciano D, Wittig M, Nothnagel M, Elger CE, Nürnberg P, Romano C, Malafosse A, Koeleman BP, Lindhout D, Stephani U, Schreiber S, Eichler EE, Sander T. 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet. 2009 Jan 11. Abstract

 
Comments on News and Primary Papers
Comment by:  Ben Pickard
Submitted 21 January 2009 Posted 21 January 2009

Before Christmas, an insightful discussion between SRF's Pete Farley and researchers Heather Mefford and Evan Eichler delved into the complex interplay between genotype (copy number variant status at 1q21.1) and phenotype (psychiatric illness, autism, mental retardation, and congenital abnormalities) (see SRF related news story). The upshot was that although deletions at this locus were statistically associated with pathologies, the severity and nature of those pathologies was extremely variable. This raised questions about whether researchers and clinicians should focus on the disease or the deletion, and what the mechanisms that determine the clinical endpoint might be. This is becoming a clear trend. Another CNV region at 16p11.2 has also been variously associated with both autism and schizophrenia. Deletions of just a single gene, CNTNAP2, as opposed to a gene cluster, have also shown this phenomenon of variable phenotype expression—deletion carriers have been diagnosed with autism, Gilles de la...  Read more


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