TY - JOUR
T1 - Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
AU - The SPARK Consortium
AU - Wang, Tianyun
AU - Hoekzema, Kendra
AU - Vecchio, Davide
AU - Wu, Huidan
AU - Sulovari, Arvis
AU - Coe, Bradley P.
AU - Gillentine, Madelyn A.
AU - Wilfert, Amy B.
AU - Perez-Jurado, Luis A.
AU - Kvarnung, Malin
AU - Sleyp, Yoeri
AU - Earl, Rachel K.
AU - Rosenfeld, Jill A.
AU - Geisheker, Madeleine R.
AU - Han, Lin
AU - Du, Bing
AU - Barnett, Chris
AU - Thompson, Elizabeth
AU - Shaw, Marie
AU - Carroll, Renee
AU - Friend, Kathryn
AU - Catford, Rachael
AU - Palmer, Elizabeth E.
AU - Zou, Xiaobing
AU - Ou, Jianjun
AU - Li, Honghui
AU - Guo, Hui
AU - Gerdts, Jennifer
AU - Avola, Emanuela
AU - Calabrese, Giuseppe
AU - Elia, Maurizio
AU - Greco, Donatella
AU - Lindstrand, Anna
AU - Nordgren, Ann
AU - Anderlid, Britt Marie
AU - Vandeweyer, Geert
AU - Van Dijck, Anke
AU - Van der Aa, Nathalie
AU - McKenna, Brooke
AU - Hancarova, Miroslava
AU - Bendova, Sarka
AU - Havlovicova, Marketa
AU - Malerba, Giovanni
AU - Bernardina, Bernardo Dalla
AU - Muglia, Pierandrea
AU - van Haeringen, Arie
AU - Hoffer, Mariette J.V.
AU - Esler, Amy
AU - Francis, Sunday
AU - Jacob, Suma
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-18723-y
DO - 10.1038/s41467-020-18723-y
M3 - Article
C2 - 33004838
AN - SCOPUS:85091936481
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4932
ER -