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Neubauer, B. A.

Publications and source records attributed to Neubauer, B. A..

2 recordsLinked to original sources
bioRxiv2017

Heterogeneous Contribution of Microdeletions in the Development of Common Generalized and Focal epilepsies

BackgroundMicrodeletions are known to confer risk to epilepsy, particularly at genomic rearrangement \"hotspot\" loci. However, deciphering their role outside hotspots and risk assessment by epilepsy sub-type has not been conducted.\n\nMethodsWe assessed the burden, frequency and genomic content of rare, large microdeletions found in a previously published cohort of 1,366 patients with Genetic Generalized Epilepsy (GGE) plus two sets of additional unpublished genome-wide microdeletions found in 281 Rolandic Epilepsy (RE) and 807 Adult Focal Epilepsy (AFE) patients, totaling 2,454 cases. These microdeletion sets were assessed in a combined analysis and in sub-type specific approaches against 6,746 ethnically matched controls.\n\nResultsWhen hotspots are considered, we detected an enrichment of microdeletions in the combined epilepsy analysis (adjusted-P= 2.00x10-7; OR = 1.89; 95%-CI: 1.51-2.35), where the implicated microdeletions overlapped with rarely deleted genes and those involved in neurodevelopmental processes. Sub-type specific analyses showed that hotspot deletions in the GGE subgroup contribute most of the signal (adjusted-P = 1.22x10-12; OR = 7.45; 95%-CI = 4.20-11.97). Outside hotspot loci, microdeletions were enriched in the GGE cohort for neurodevelopmental genes (adjusted-P = 4.78x10-3; OR = 2.30; 95%-CI = 1.42-3.70), whereas no additional signal was observed for RE and AFE. Still, gene content analysis was able to identify known (NRXN1, RBFOX1 and PCDH7) and novel (LOC102723362) candidate genes affected in more than one epilepsy sub-type but not in controls.\n\nConclusionsOur results show a heterogeneous effect of recurrent and non-recurrent microdeletions as part of the genetic architecture of GGE and a minor to negligible contribution in the etiology of RE and AFE.

genetics↗
bioRxiv2017

Duplications at 19q13.33 in patients with neurodevelopmental disorders

OBJECTIVEAfter recent publication of the first patients with disease associated missense variants in GRIN2D, we evaluate the effect of copy number variation (CNV) overlapping this gene towards the presentation of neurodevelopmental disorders.\n\nMETHODSWe explored ClinVar (N{degrees}CNV = 41,398) and DECIPHER (N{degrees}CNV = 30,222) clinical databases of genomic variations for patients with copy number changes overlapping the GRIN2D gene at the 19q13.33 locus and evaluated their respective phenotype alongside their frequency, gene content and expression with publicly available reference databases.\n\nRESULTSWe identified 13 patients with microduplications at the 19q13.33 locus. The majority of CNVs arose de novo and comparable CNVs are not present in control databases. All patients were reported to have neurodevelopmental disorders and dysmorphic features as the most common clinical phenotype (N= 10/13), followed by seizures (N= 6/13) and intellectual disability (N= 5/13). All duplications shared a consensus region of 405 kb overlapping 13 genes. After screening for duplication tolerance in control populations, positive gene brain expression and gene dosage sensitivity analysis, we highlight four genes for future evaluation: CARD8, C19orf68, KDELR1 and GRIN2D, which are promising candidates for disease causality. Further, investigation of the literature especially supports GRIN2D as the best candidate gene.\n\nCONCLUSIONSOur study presents dup19q13.33 as novel duplication syndrome locus associated with neurodevelopmental disorders. CARD8, C19orf68, KDELR1 and GRIN2D are promising candidates for functional follow up.

genetics↗