Whole Exome Sequencing Identifies Novel De Novo Variants Interacting with Six Gene Networks in Autism Spectrum Disorder
Abstract
:1. Introduction
2. Methods
2.1. Subject Ascertainment and Ethnic Information
2.2. Study Design and Bioinformatics Analysis
2.3. Variant Discovery and Filtering
2.4. Gene Network Analysis
2.5. Genetic Validation using Sanger Sequencing
3. Results
3.1. Network A. DTX1, MTUS1, RASGRP1, and RUFY1
3.2. Network B. ADCY7, ATXN1, IWS1, KCTD9, MT-ND2, NFKB1, and PPP1R16B
3.3. Network C. AMIGO1, HAX1, MYH14, RNH1, SNF8, and SYNM
3.4. Network D. AKNA, GMIP, LARS2, NEK1, and TFPT
3.5. Network E. CELSR3, COL6A2, HMGXB4, PIEZO1, RBM27, SFMBT2, and UBAC1
3.6. Network F. ANKRD27, TMEM8A, and TTC21A
3.7. Evidence from Topologically Associating Domain (TAD) in TFPT and HAX1
4. Discussion
Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
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Clinical Characteristics | First Stage (n = 13) | Second Stage (n = 38) | |||
---|---|---|---|---|---|
Mean | SD | Mean | SD | ||
Age (months) | 59.50 | 12.41 | 73.53 | 29.94 | |
Sex (number of females) | 0 | 4 | |||
ADI-R | social interaction | 24.33 | 3.65 | 22.05 | 5.67 |
communication: verbal | 18.43 | 5.68 | 18.58 | 4.50 | |
communication: nonverbal | 12.00 | 2.73 | 11.71 | 2.34 | |
repetitive behavior | 6.50 | 2.71 | 5.74 | 2.58 | |
ADOS | Communication | 6.67 | 1.23 | 6.05 | 1.23 |
social interaction | 10.25 | 2.34 | 10.16 | 2.15 | |
Play | 2.92 | 1.24 | 2.34 | 1.17 | |
repetitive behavior | 3.00 | 1.65 | 2.50 | 1.39 | |
KEDI-WISC-R | 43.00 | 33.41 | 57.47 | 15.88 | |
K-Leiter-R | 78.86 | 25.60 | 62.56 | 25.64 | |
SCQ | 23.75 | 5.55 | 19.97 | 7.71 | |
SRS | 109.08 | 27.62 | 95.08 | 31.05 |
Genomic Position | Gene Symbol | dbSNP RS ID | REF>ALT Allele | Sequence Variant Nomenclature (2) | Variant Type | Probands (:occur.) |
---|---|---|---|---|---|---|
(GRCh38/hg38) (1) | Build 154 | |||||
chr1:109507558 | AMIGO1 | C>A | ENST00000369864.5 c.1355G>T/p.Gly452Val | Missense | B34 | |
chr1:154274980 | HAX1 | C>A | ENST00000328703.11|ENST00000457918.6 c.535C>A|c.391C>A/p.Pro179Thr|p.Pro131Thr | Missense | B15 | |
chr2:127493330 | IWS1 | C>G | ENST00000295321.9|ENST00000637187.1 c.1880G>C|c.47G>C/p.Ser627Thr|p.Ser16Thr | Missense | B5 :1st | |
chr3:39112529 | TTC21A | C>A | ENST00000431162.6 c.507C>A/p.Tyr169 * | Nonsense | B16 | |
chr3:45513187 | LARS2 | rs147745374 | C>T | ENST00000415258.6 c.1813C>T/p.Arg605Cys | Missense | B1 |
chr3:48645607 | CELSR3 | rs756781285 | C>T | ENST00000164024.5 c.7633G>A/p.Val2545Met | Missense | A12 :1st |
chr4:990079 | SLC26A1 | rs748023701 | C>T | ENST00000361661.6 c.860G>A/p.Arg287His | Missense | B27 |
chr4:102607251 | NFKB1 | rs934744465 | G>A | ENST00000394820.8 c.2053G>A/p.Gly685Arg | Missense | B25 :1st |
chr4:169602542 | NEK1 | rs200825809 | T>C | ENST00000507142.5 c.89A>G/p.Tyr30Cys | Missense | B11 |
chr5:146233644 | RBM27 | C>A | ENST00000265271.7 c.1045C>A/p.Pro349Thr | Missense | B26 :1st | |
chr5:179609380 | RUFY1 | A>G | ENST00000393438.6 c.1664A>G/p.His555Arg | Missense | B29 | |
chr6:16306637 | ATXN1 | C>T | ENST00000244769.8 c.2140G>A/p.Asp714Asn | Missense | B26 :2nd | |
chr6:44282283 | TCTE1 | rs746423492 | C>T | ENST00000371505.5 c.1123G>A/p.Glu375Lys | Missense | A4 |
chr8:17697396 | MTUS1 | rs377560516 | G>A | ENST00000297488.10 c.-19C>T/5’UTR | 5’UTR | B26 :3rd |
chr8:25436242 | KCTD9 | rs1448423271 | C>T | ENST00000221200.9 c.656G>A/p.Arg219Gln | Missense | A9 |
chr9:114342063 | AKNA | A>T | ENST00000307564.8 c.3820T>A/p.Cys1274Ser | Missense | A12 :2nd | |
chr9:135939739 | UBAC1 | C>A | ENST00000371756.3 c.897G>T/p.Glu299Asp | Missense | B10 :1st | |
chr10:3141725 | PITRM1-AS1 | G>A | ENST00000430356.3 (PITRM1-AS1, Antisense) ENST00000451454.5 (PITRM1, Intronic) | Antisense/Intronic | B25 :2nd | |
chr10:7370280 | SFMBT2 | rs1373335289 | C>T | ENST00000361972.8 c.195+1G>A/Splice Donor Variant | Splice Site | B5 :2nd |
chr11:499976 | RNH1 | C>T | ENST00000534797.5 c.296G>A/p.Gly99Glu | Missense | B33 | |
chr12:113094062 | DTX1 | rs1232450939 | G>A | ENST00000257600.3 c.1190G>A/p.Arg397Gln | Missense | B6 |
chr15:38516208 | RASGRP1 | rs1595848108 | G>A | ENST00000310803.10 c.664C>T/p.Arg222Trp | Missense | B12 |
chr15:99131660 | SYNM | rs782771735 | G>A | ENST00000336292.10 c.3300G>A/p.Ser1100Ser | Silent | B18 |
chr16:377706 | TMEM8A | C>G | ENST00000431232.7 c.264G>C/p.Glu88Asp | Missense | B25 :3rd | |
chr16:50293480 | ADCY7 | rs199730202 | G>A | ENST00000254235.7 c.814G>A/p.Val272Ile | Missense | B10 :2nd |
chr16:88738626 | PIEZO1 | rs1475582880 | GGCCGTGACTCGGAAACGAGCGGCCA>G | ENST00000301015.14 c.551_575delTGGCCGCTCGTTTCCGAGTCACGGC/p.Leu184fs | Frameshift Deletion | B3 |
chr17:48937128 | SNF8 | C>T | ENST00000502492.5 c.245-4G>A/Spice Region Variant | Splice Region | B25 :4th | |
chr19:19637386 | GMIP | T>A | ENST00000203556.9 c.1103A>T/p.Glu368Val | Missense | B21 :1st | |
chr19:32628120 | ANKRD27 | G>C | ENST00000306065.9 c.1383C>G/p.Asp461Glu | Missense | B21 :2nd | |
chr19:50257343 | MYH14 | rs778416774 | G>A | ENST00000599920.5 c.1990G>A/p.Gly664Ser | Missense | A3 |
chr19:54107093 | TFPT | TTGTC>T | ENST00000391759.5 c.715_718delGACA/p.Asp239fs | Frameshift Deletion | B4 | |
chr20:32453760 | NOL4L | rs749152593 | G>C | ENST00000359676.9 c.389C>G/p.Ser130Cys | Missense | B9 |
chr20:38902679 | PPP1R16B | G>A | ENST00000299824.6 c.583G>A/p.Glu195Lys | Missense | B7 | |
chr21:46121590 | COL6A2 | rs267606749 | G>A | ENST00000300527.8 c.1493G>A/p.Arg498His | Missense | B37 |
chr22:35265292 | HMGXB4 | C>G | ENST00000455359.5 c.577C>G/p.Leu193Val | Missense | B32 :1st | |
chrM:4943 | MT-ND2 | rs1603219681 | A>G | ENST00000361453.3 c.474A>G/p.Ser158Ser | Silent | B32 :2nd |
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Kim, N.; Kim, K.H.; Lim, W.-J.; Kim, J.; Kim, S.A.; Yoo, H.J. Whole Exome Sequencing Identifies Novel De Novo Variants Interacting with Six Gene Networks in Autism Spectrum Disorder. Genes 2021, 12, 1. https://doi.org/10.3390/genes12010001
Kim N, Kim KH, Lim W-J, Kim J, Kim SA, Yoo HJ. Whole Exome Sequencing Identifies Novel De Novo Variants Interacting with Six Gene Networks in Autism Spectrum Disorder. Genes. 2021; 12(1):1. https://doi.org/10.3390/genes12010001
Chicago/Turabian StyleKim, Namshin, Kyoung Hyoun Kim, Won-Jun Lim, Jiwoong Kim, Soon Ae Kim, and Hee Jeong Yoo. 2021. "Whole Exome Sequencing Identifies Novel De Novo Variants Interacting with Six Gene Networks in Autism Spectrum Disorder" Genes 12, no. 1: 1. https://doi.org/10.3390/genes12010001