Rare Deletions at 16p13.11 Predispose to a Diverse Spectrum of Sporadic Epilepsy Syndromes

Erin L Heinzen,Julie Huxley-Jones,Sarah K Tate,Dongliang Ge,David B Goldstein,Günter Krämer,Josemir W Sander,Jörg Hansen,Kai Eriksson,Colin P Doherty,Aatif M Husain,Jessica M Maia,Massimo Pandolfo,Rachel A Gibson,Claudia B Catarino,Kristen N Linney,Ray L Stallings,Nicole M Walley,Bernhard J Steinhoff,Michael R Johnson,Rodney A Radtke,Sanjay M Sisodiya,Kevin V Shianna,Thomas Dorn,Paul M Matthews,Reetta Kälviäinen,Norman Delanty,Marcos Ortega,Nicholas W Wood,Patrick G Buckley,John S Duncan,Paola Nicoletti,Mihai V Podgoreanu,David Leppert,Dominik Zumsteg,Anna C Need,Anne-Mari Kantanen,Gianpiero L Cavalleri,William B Gallentine,Chantal Depondt,Dalia Kasperavičiūtė ,Thomas Urban ,Luís Otávio Sales Ferreira Caboclo ,Lisa M Clayton ,Jason P Smith ,Kenneth Cronin ,Lefkos Middleton ,Mohamad A Mikati ,David A Hosford ,Curtis Gumbs ,Heinz‐Gregor Wieser

doi:10.1016/j.ajhg.2010.03.018

Abstract

Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions.

Highlights

The absence of 15q13.3 deletions in any of the more than 3000 focal epilepsy patients suggests that its involvement in epilepsy disorders is specific to generalized forms, despite the fact that deletions in this region have been associated with nonspecific effects in neuropsychiatric disease risk.[3,7,12]
Two of the 24 patients (~8%) with a deletion greater than 300 kb in the previously reported risk region had a diagnosis of generalized epilepsy, which is approximately equal to the percentage of patients with generalized epilepsy disorders in the cohort studied
Despite the increasing reports of associations of copy number variants (CNVs) with neurological, psychiatric, and developmental disorders, very little is known about the functional mechanisms that result in disease susceptibility

Summary

Introduction

Common SNPs have been shown to play at most a modest role in most neuropsychiatric diseases, a growing body of evidence connects large deletions and duplications, or copy number variants (CNVs), to schizophrenia, autism, and mental retardation.[1,2,3,4,5] Recently, deletions at 15q13.3 and 16p13.11, previously implicated in schizophrenia[2] and mental retardation,[6] have been associated with idiopathic generalized epilepsy.[7,8] These findings add epilepsy to the growing list of neuropsychiatric conditions with overlapping susceptibility conferred by copy number variation.Here, we report a genome-wide screen evaluating the role of large, rare CNVs in patients affected with a wide range of seizure disorders, including both partial andThe American Journal of Human Genetics 86, 707–718, May 14, 2010 707 generalized seizure disorders. Common SNPs have been shown to play at most a modest role in most neuropsychiatric diseases, a growing body of evidence connects large deletions and duplications, or copy number variants (CNVs), to schizophrenia, autism, and mental retardation.[1,2,3,4,5] Recently, deletions at 15q13.3 and 16p13.11, previously implicated in schizophrenia[2] and mental retardation,[6] have been associated with idiopathic generalized epilepsy.[7,8] These findings add epilepsy to the growing list of neuropsychiatric conditions with overlapping susceptibility conferred by copy number variation. We report a genome-wide screen evaluating the role of large, rare CNVs in patients affected with a wide range of seizure disorders, including both partial and.

Methods

Results

Conclusion