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De novo and inherited private variants in MAP1B in periventricular nodular heterotopia.
Heinzen EL1, O'Neill AC2, Zhu X1, Allen AS3,4, Bahlo M5,6, Chelly J7,8, Chen MH9, Dobyns WB10,11, Freytag S12, Guerrini R13, Leventer RJ14,15,16, Poduri A17, Robertson SP2, Walsh CA18,19,20, Zhang M4,21; Epi4K Consortium; Epilepsy Phenome/Genome Project.
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Abstract
Periventricular nodular heterotopia (PVNH) is a malformation of cortical development commonly associated with epilepsy. We exome sequenced 202 individuals with sporadic PVNH to identify novel genetic risk loci. We first performed a trio-based analysis and identified 219 de novo variants. Although no novel genes were implicated in this initial analysis, PVNH cases were found overall to have a significant excess of nonsynonymous de novo variants in intolerant genes (p = 3.27x10-7), suggesting a role for rare new alleles in genes yet to be associated with the condition. Using a gene-level collapsing analysis comparing cases and controls, we identified a genome-wide significant signal driven by four ultra-rare loss-of-function heterozygous variants in MAP1B, including one de novo variant. In at least one instance, the MAP1B variant was inherited from a parent with previously undiagnosed PVNH. The PVNH was frontally predominant and associated with perisylvian polymicrogyria. These results implicate MAP1B in PVNH. More broadly, our findings suggest that detrimental mutations likely arising in immediately preceding generations with incomplete penetrance may also be responsible for some apparently sporadic diseases.
www.ncbi.nlm.nih.gov/pubmed/29738522
De novo e varianti private ereditate in MAP1B nell'eterotopia nodulare periventricolare.
Heinzen EL1, O'Neill AC2, Zhu X1, Allen AS3,4, Bahlo M5,6, Chelly J7,8, Chen MH9, Dobyns WB10,11, Freytag S12, Guerrini R13, Leventer RJ14,15,16, Poduri A17, Robertson SP2, Walsh CA 18,19,20, Zhang M4,21; Consorzio Epi4K; Progetto di fenomenologia / genoma dell'epilessia.
Informazioni sull'autore
Astratto
L'eterotopia nodulare periventricolare (PVNH) è una malformazione dello sviluppo corticale comunemente associata all'epilessia. Esaminiamo sequenzialmente 202 individui con PVNH sporadico per identificare nuovi loci di rischio genetico. Per prima cosa abbiamo eseguito un'analisi basata su trio e identificato 219 varianti de novo. Sebbene in questa analisi iniziale non siano stati implicati nuovi geni, i casi di PVNH sono stati riscontrati nel complesso con un eccesso significativo di varianti de novo non sinonime nei geni intolleranti (p = 3.27x10-7), suggerendo un ruolo per rari nuovi alleli nei geni ancora da associato alla condizione. Utilizzando un'analisi collassante a livello genico confrontando casi e controlli, abbiamo identificato un segnale significativo dell'intero genoma guidato da quattro varianti di eterozigoti con perdita di funzione ultra-rare in MAP1B, inclusa una variante de novo. In almeno un'istanza, la variante MAP1B è stata ereditata da un padre con PVNH precedentemente non diagnosticato. Il PVNH era predominante frontalmente e associato a polimicrogiria perisilviana. Questi risultati implicano MAP1B in PVNH. Più in generale, i nostri risultati suggeriscono che mutazioni dannose probabilmente derivanti da generazioni immediatamente precedenti con penetranza incompleta possono anche essere responsabili di alcune malattie apparentemente sporadiche.
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Quantile-quantile plot for gene-level association tests interrogating LoF variants.
Black dots represent transformed p values against the expected transformed p values for genes with qualifying LoF variants. The red dot corresponds to the p value associated with SON however all four variants driving this signal were found to be false positives with Sanger sequencing. The red line indicates the expectation under the null model of no effect on risk.
Distribution of MAP1B LOF alleles in PVNH cases (red dots), in individuals from ExAC and gnomAD databases (blue dots with number of alleles observed represented by number of dots running vertically at this site), and in the Deciphering Developmental Disorders case (orange dot).
A Sanger confirmed de novo variant is indicated with a white dot in the circle.
Brain MRI of subjects pvhnz9000cfc1 (top) and mother (bottom).
Images are coronal T1-weighted (left column) and axial T1-weighted (right column). The images all show bilateral periventricular nodular grey matter heterotopia maximal in the frontal regions (black arrows). The axial images show over-folded cortex in the deep perisylvian/insular region on the right consistent with polymicrogyria (white arrows).
Ordered correlation matrices for the PVNH query and the fourteen loci significantly co-expressing within this node.
Pairwise Pearson’s correlation represented as a matrix between (a) pairs of the 14 genes within the PVNH gene set (Methods) and (b) the human PVNH query plus the 14 genes whose co-regulatory patterns significantly exceed the eFDR in both the Kang and Miller transcriptomic datasets. Genes are ordered according to hierarchical clustering, with the most positive (+1) and negative (-1) co-regulatory interactions represented as blue and red squares, respectively.
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