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