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Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders.

ABSTRACT: Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.

SUBMITTER: Wang T

PROVIDER: S-EPMC7530681 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders.

Wang Tianyun T Hoekzema Kendra K Vecchio Davide D Wu Huidan H Sulovari Arvis A Coe Bradley P BP Gillentine Madelyn A MA Wilfert Amy B AB Perez-Jurado Luis A LA Kvarnung Malin M Sleyp Yoeri Y Earl Rachel K RK Rosenfeld Jill A JA Geisheker Madeleine R MR Han Lin L Du Bing B Barnett Chris C Thompson Elizabeth E Shaw Marie M Carroll Renee R Friend Kathryn K Catford Rachael R Palmer Elizabeth E EE Zou Xiaobing X Ou Jianjun J Li Honghui H Guo Hui H Gerdts Jennifer J Avola Emanuela E Calabrese Giuseppe G Elia Maurizio M Greco Donatella D Lindstrand Anna A Nordgren Ann A Anderlid Britt-Marie BM Vandeweyer Geert G Van Dijck Anke A Van der Aa Nathalie N McKenna Brooke B Hancarova Miroslava M Bendova Sarka S Havlovicova Marketa M Malerba Giovanni G Bernardina Bernardo Dalla BD Muglia Pierandrea P van Haeringen Arie A Hoffer Mariette J V MJV Franke Barbara B Cappuccio Gerarda G Delatycki Martin M Lockhart Paul J PJ Manning Melanie A MA Liu Pengfei P Scheffer Ingrid E IE Brunetti-Pierri Nicola N Rommelse Nanda N Amaral David G DG Santen Gijs W E GWE Trabetti Elisabetta E Sedláček Zdeněk Z Michaelson Jacob J JJ Pierce Karen K Courchesne Eric E Kooy R Frank RF Nordenskjöld Magnus M Romano Corrado C Peeters Hilde H Bernier Raphael A RA Gecz Jozef J Xia Kun K Eichler Evan E EE

Nature communications 20201001 1

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reporte ...[more]

PMID: 33004838

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Project description:A major goal of maize genomic research is to identify sequence polymorphisms responsible for phenotypic variation in traits of economic importance. Large-scale detection of sequence variation is critical for linking genes, or genomic regions, to phenotypes. However, due to its size and complexity, it remains expensive to generate whole genome sequences of sufficient coverage for divergent maize lines, even with access to next generation sequencing (NGS) technology. Because methods involving reduction of genome complexity, such as genotyping-by-sequencing (GBS), assess only a limited fraction of sequence variation, targeted sequencing of selected genomic loci offers an attractive alternative. We therefore designed a sequence capture assay to target 29 Mb genomic regions and surveyed a total of 4,648 genes possibly affecting biomass production in 21 diverse inbred maize lines (7 flints, 14 dents). Captured and enriched genomic DNA was sequenced using the 454 NGS platform to 19.6-fold average depth coverage, and a broad evaluation of read alignment and variant calling methods was performed to select optimal procedures for variant discovery. Sequence alignment with the B73 reference and de novo assembly identified 383,145 putative single nucleotide polymorphisms (SNPs), of which 42,685 were non-synonymous alterations and 7,139 caused frameshifts. Presence/absence variation (PAV) of genes was also detected. We found that substantial sequence variation exists among genomic regions targeted in this study, which was particularly evident within coding regions. This diversification has the potential to broaden functional diversity and generate phenotypic variation that may lead to new adaptations and the modification of important agronomic traits. Further, annotated SNPs identified here will serve as useful genetic tools and as candidates in searches for phenotype-altering DNA variation. In summary, we demonstrated that sequencing of captured DNA is a powerful approach for variant discovery in maize genes.

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Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders.

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Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders.

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