Family-Based Whole-Exome Analysis of Specific Language Impairment (SLI) Identifies Rare Variants in BUD13, a Component of the Retention and Splicing (RES) Complex
Abstract
1. Introduction
2. Materials and Methods
2.1. Participants
2.1.1. Family 489
2.1.2. Additional Participants
2.1.3. Phenotype
2.2. Genetic Analyses
2.2.1. DNA Collection and Preparation
2.2.2. Whole-Exome Sequencing and Data Analysis
2.2.3. Prioritization of Rare Variants in the WES
2.2.4. Identification of Candidate Genes, Confirmation, and Significance Testing
Fam 489 Variants | Additional Variants | |||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Previous Candidates | Co-Segregating | NDRG2 | APLP2 | BUD13 | ||||||||||||||||
Evidence Class | Evidence | KIAA0319 rs113411083 | FLNC rs202223616 | NOP9 rs183868211 | NDRG2 rs11552412 | APLP2 rs370970986 | BUD13 rs139478949 | rs779725845 | rs1063201 | chr11:129992279 | rs201861910 | rs35585096 | rs116087150 | rs1467808735 | rs144776650 | rs11216131 | rs1427011653 | rs145410701 | rs61730763 | rs145906707 |
Genetic | MAF ≤ 0.05 | + | + | − | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + |
Co-segregation | − | − | − | + | + | + | − | − | − | + | − | − | − | − | − | − | − | − | + | |
≥1 proband | − | − | + | − | − | − | − | − | − | − | + | − | − | + | − | − | − | − | + | |
Informatic | Positive GERP Score | + | + | + | + | + | + | + | − | + | − | + | + | + | − | + | − | − | + | + |
Total # of damaging in silico scores | 2 | 1 | 0 | 4 | 2 | 4 | 2 | 0 | 2 | NA | 2 | 4 | 4 | 1 | 5 | 0 | 0 | 3 | NA | |
HOPE output/AA change | ||||||||||||||||||||
Size | ∧ | ∧ | ∨ | ∧ | ∧ | ∨ | ∧ | ∧ | ∧ | NA | ∧ | ∨ | ∨ | ∨ | ∨ | ∧ | ∨ | ∧ | NA | |
>Hydrophobic | + | − | + | + | − | − | + | − | − | NA | + | + | + | − | + | − | + | − | NA | |
Charge change | pos | neg | pos | neu | NC | pos | NC | NC | neg | NA | NC | pos | neu | pos | pos | NC | NC | NC | NA | |
to | to | to | to | to | to | to | to | to | to | |||||||||||
neu | pos | neu | neg | neu | pos | neu | neg | neu | neu | |||||||||||
Causality | P | B | B | P | P | P | P | B | P | NA | P | P | P | B | P | B | B | P | NA |
3. Results
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gene | Genomic Position (hg19) | c.DNA Variant | AA Change | rsID | IDs of SLI Probands with Variant n = 175 | MAF in gnomAD | In Silico Prediction Scores | |||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Glob | Euro | SIFT | Poly Phen-2 | Mutation assessor | PROVEAN | Mutation Taster | ||||||
KIAA0319 | Chr6: | c.2164G > A | p.Arg722Trp | rs113411083 | NA | 0.00275 | 0.0047 | 0.068 | 0.998 | 1.495 | −3.28 | 101 |
24566953 | (T) | prob D | (low) | D | P | |||||||
FLNC | Chr7: | c.6808G > A | p.Glu2270Lys | rs202223616 | NA | 0.00073 | 0.00168 | 1 | 0.371 | 1.23 | −2.44 | 56 |
128494547 | (T) | B | (low) | N | DC | |||||||
NOP9 | Chr14: | c.62G > C | p.Arg21Pro | rs183868211 | 346, 353, 355, 411, 472 | 0.00936 | 0.02304 | 0.147 | 0.01 | 2.39 | −0.94 | 103 |
24769222 | (T) | B | (med) | N | P |
Gene | Genomic Position (hg19) | c.DNA Variant | AA Change | rsID | IDs of SLI Probands with Variant n = 175 | MAF in gnomAD | In Silico Prediction Scores | |||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Glob | Euro | SIFT | Poly Phen-2 | Mutation Assessor | PROVEAN | Mutation Taster | ||||||
BUD13 | Chr11: | c.689G > A | p.Arg230Glu | rs139478949 | NA | 0.00002 | 0.00005 | 0.013 | 0.934 | 3.405 | −2.51 | 43 |
116633616 | (D) | poss D | (med) | D | DC | |||||||
APLP2 | Chr11: | c.2041G > A | p.Val681Met | rs370970986 | NA | 0.00002 | 0.00002 | 0.39 | 0.94 | 1.1 | −0.01 | 21 |
130011820 | (D) | poss D | (low) | N | P | |||||||
NDRG2 | Chr14: | c.143G > A | p.Gly48Asp | rs11552412 | NA | NA | NA | 0 | 1.00 | 3.445 | −6.06 | 94 |
21490631 | (D) | prob D | (med) | D | DC |
Genomic Position (hg19) Chr11 | c.DNA | AA Change | rsID | IDs of SLI Probands with Variant n = 175 | MAF in gnomAD | In Silico Prediction Scores | |||||
---|---|---|---|---|---|---|---|---|---|---|---|
Glob | Euro | SIFT | Poly Phen-2 | Mutation Assessor | PROVEAN | Mutation Taster | |||||
129991652 | c.660T > G | p.Asp220Glu | rs1063201 | 434 | 0.00006 | 0.00002 | 0.736 | 0 | 0.255 | −0.59 | 45 |
(T) | B | (neutral) | N | P | |||||||
129992279 | c.793G > A | p.Glu265Lys | NA | 463 | NA | NA | 0.022 | 0 | 0.55 | −1.54 | 56 |
(D) | B | (neutral) | N | DC | |||||||
130013358 | c.*15G > A | 3′UTR | rs201861910 | 447 | 0.001221 | 0.001972 | NA | NA | NA | NA | NA |
Genomic Position (hg19) Chr11 | c.DNA | AA Change | rsID | IDs of SLI Probands with Variant n = 175 | MAF in gnomAD | In Silico Prediction Scores | |||||
---|---|---|---|---|---|---|---|---|---|---|---|
Glob | Euro | SIFT | Poly Phen-2 | Mutation Assessor | PROVEAN | Mutation Taster | |||||
116643617 | c.64C > A | p.Ala22Ser | rs35585096 | 337, 455, 483, 405 | 0.023 | 0.000 | 0.112 | 0.578 | 2.44 | −0.81 | 99 |
(D) | poss D | (med) | N | P | |||||||
116633875 | c.430G > A | p.Arg144Cys | rs116087150 | 49324 | 0.000 | 0.000 | 0.045 | 1 | 2.81 | −4.15 | 180 |
(D) | prob D | (med) | D | DC | |||||||
116633787 | c.518T > C | p.Asp173Gly | rs1467808735 | 360 | 0.000 | 0.000 | 0.013 | 1 | 3.27 | −4.47 | 94 |
(D) | prob D | (med) | D | DC | |||||||
116633724 | c.581C > T | p.Arg194His | rs144776650 | 384, 422, 484 | 0.003 | 0.005 | 0.06 | 0.091 | 1.725 | −3.73 | 29 |
(T) | B | (low) | D | P | |||||||
116633580 | c.725C > A | p.Arg242Ile | rs11216131 | 500 | 0.001 | 0.001 | 0.002 | 0.999 | 3.58 | −4.43 | 97 |
(D) | prob D | (high) | D | DC | |||||||
116633425 | c.880C > G | p.Ala294Pro | rs1427011653 | 201 | NA | NA | 0.231 | 0.002 | 2.395 | −0.75 | 27 |
(T) | B | (med) | N | P | |||||||
116633353 | c.952A > T | p.Tyr318Asn | rs145410701 | 438 | 0.001 | 0.000 | 0.33 | 0.138 | 2.045 | −1.26 | 142 |
(T) | B | (med) | N | P | |||||||
116631482 | c.1223G > A | p.Pro408Leu | rs61730763 | 427 | 0.003 | 0.000 | 0.023 | 0.275 | 2.63 | −7.04 | 98 |
(D) | B | (med) | D | DC | |||||||
116619178 | c.*20G > A | 3′UTR | rs145906707 | 431, 447 | 0.003 | 0.003 | NA | NA | NA | NA | NA |
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Andres, E.M.; Earnest, K.K.; Zhong, C.; Rice, M.L.; Raza, M.H. Family-Based Whole-Exome Analysis of Specific Language Impairment (SLI) Identifies Rare Variants in BUD13, a Component of the Retention and Splicing (RES) Complex. Brain Sci. 2022, 12, 47. https://doi.org/10.3390/brainsci12010047
Andres EM, Earnest KK, Zhong C, Rice ML, Raza MH. Family-Based Whole-Exome Analysis of Specific Language Impairment (SLI) Identifies Rare Variants in BUD13, a Component of the Retention and Splicing (RES) Complex. Brain Sciences. 2022; 12(1):47. https://doi.org/10.3390/brainsci12010047
Chicago/Turabian StyleAndres, Erin M., Kathleen Kelsey Earnest, Cuncong Zhong, Mabel L. Rice, and Muhammad Hashim Raza. 2022. "Family-Based Whole-Exome Analysis of Specific Language Impairment (SLI) Identifies Rare Variants in BUD13, a Component of the Retention and Splicing (RES) Complex" Brain Sciences 12, no. 1: 47. https://doi.org/10.3390/brainsci12010047
APA StyleAndres, E. M., Earnest, K. K., Zhong, C., Rice, M. L., & Raza, M. H. (2022). Family-Based Whole-Exome Analysis of Specific Language Impairment (SLI) Identifies Rare Variants in BUD13, a Component of the Retention and Splicing (RES) Complex. Brain Sciences, 12(1), 47. https://doi.org/10.3390/brainsci12010047