Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Tianyun Wang ,Šárka Bendová ,Jill A Rosenfeld ,Pierandrea Muglia ,Paul J Lockhart ,Amy B Wilfert ,Jozef Gécz ,Bing Du ,Yoeri Sleyp ,Giuseppe Calabrese ,Zdeněk Sedláček ,Honghui Li ,Jianjun Ou ,Maurizio Elia ,Gijs W.e Santen ,Brooke G Mckenna ,Xiaobing Zou ,Davide Vecchio ,Giovanni Malerba ,Arvis Sulovari ,Britt‐Marie Anderlid ,Kun Xia ,Anke Van Dijck ,Martin B Delatycki ,Jacob J Michaelson ,Kathryn Friend ,Mariëtte J.v Hoffer ,Raphael Bernier ,Barbara Franke ,Ann Nordgren ,Hui Guo ,Kendra Hoekzema ,Han Lin ,Nanda Rommelse ,Luis A Pérez‐Jurado ,Bradley P Coe ,Nathalie Van Der Aa ,Madeleine R Geisheker ,Emanuela Avola ,Gerarda Cappuccio ,Geert Vandeweyer ,Corrado Romano ,Pengfei Liu ,Arie Van Haeringen ,Rachel K Earl ,Renée Carroll ,Chris Barnett ,Jennifer Gerdts ,Nicola Brunetti‐Pierri ,Miroslava Hančárová ,Elizabeth E Palmer ,R Frank Kooy ,Melanie A Manning ,Huidan Wu ,Anna Wedell ,E A Thompson ,Rachael Catford ,Donatella Greco ,Elisabetta Trabetti ,Madelyn A Gillentine ,Magnus Nordenskjöld ,Hilde Peeters ,Karen Pierce ,Bernardo Dalla Bernardina ,Marie Shaw ,David G Amaral ,Malin Kvarnung ,Eric Courchesne ,Ingrid E Scheffer ,Markéta Havlovičová ,Evan E Eichler

doi:10.1038/s41467-020-18723-y

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.

Highlights

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
The first panel (NDD1) consisted of 65 candidate genes selected for the first time in our study for sequencing in 17,832 NDD cases; the second panel represented 62 genes, generally regarded as higher confidence NDD risk genes that had already been sequenced in a smaller subset (12,000–14,000) of Autism Spectrum/Intellectual Disability (ASID) samples[3,4,5]
Transmission was successfully assessed for 110 variants where we identified 40 DNMs with 29 de novo likely gene-disruptive (LGD), 11 de novo MIS30 variants, and 70 inherited variants in 73 families with maternally inherited variants in 37 families (30 MIS30 and 7 LGD) and paternally inherited variants in 36 families (23 MIS30 and 13 LGD)

Summary

Introduction

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. 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 reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 48 genes (25 newly reported) showing significant mutation burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%) by comparing to ExAC nonpsychiatric controls Among these 125 targeted genes, we identify 90 genes enriched for DNMs (FDR 5%) by reevaluating DNM excess in 17,426 NDD trios, including 6499 new autism trios. With this large-scale targeted sequencing effort, we further double the number of patients for many NDD risk genes and present deep phenotype–genotype correlations for seven NDD risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1)

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Conclusion