Novel Mutations Detection with Next-Generation Sequencing and Its Association with Clinical Outcome in Unilateral Primary Aldosteronism
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Population
2.2. Mutation Analysis
2.3. Bioinformatics Analysis
2.4. Pathogenicity Criteria for Filtered Variants
2.5. Clinical Parameters
2.6. Clinical and Biochemical Success after Unilateral Adrenalectomy
2.7. Tissue Immunohistochemistry
2.8. Statistical Analysis
3. Results
3.1. Identification of Somatic Mutations in uPA
3.2. Phenotypic Characteristics of uPA Patients with Negative Sanger Sequencing Results
3.3. Histopathologic Characteristics of Adrenal Tumoral Tissues of uAPA
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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No. | NGS-Identified Mutated Gene | Chr | Ref | Alt | Amino Acid Change | VAF | CADD Score | M-C | M-C Pred | PP2 Score | PP2_ Pred | MSC-PP2 Score | MSC-PP2 Pred | SIFT Score | SIFT Pred |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | ATP1A1 | 1 | C | A | Leu670Ile | 5.07 | 25.9 | 17.8 | high | 0.978 | P | 0.239 | high | 0.01 | D |
2 | ATP2B3 | X | G | A | Gly1189Ser | 12.56 | 25.7 | 3.313 | high | 0.901 | P | 0.239 | high | 0 | n/a |
3 | ATP2B3 | X | G | A | Gly1189Ser | 12.56 | 25.7 | 3.313 | high | 0.901 | P | 0.239 | high | 0 | n/a |
4 | ATP2B3 | X | T | C | Phe868Leu | 5.15 | 24.7 | 3.313 | high | 0.415 | benign | 0.239 | high | n/a | n/a |
5 | CACNA1D | 3 | G | A | Val1373Met | 5.59 | 33 | 16.36 | high | 1 | P | 0.57 | high | 0 | D |
6 | CACNA1D | 3 | G | A | Val1373Met | 20.35 | 33 | 16.36 | high | 1 | P | 0.57 | high | 0 | D |
7 | CACNA1D | 3 | C | T | Ser672Leu | 39.75 | 35 | 16.36 | high | 0.992 | P | 0.57 | high | 0 | D |
8 | CACNA1D | 3 | C | T | Arg240Cys | 5.58 | 35 | 16.36 | high | 1 | P | 0.57 | high | 0 | D |
9 | CACNA1D | 3 | G | A | Met590Ile | 5.56 | 30 | 16.36 | high | 0.917 | P | 0.57 | high | 0 | D |
10 | CACNA1D | 3 | T | C | Leu248Pro | 5.14 | 28 | 16.36 | high | 1 | P | 0.57 | high | 0 | D |
11 | CACNA1D | 3 | G | A | Ala2109Thr | 8.25 | 28.7 | 16.36 | high | 0.999 | P | 0.57 | high | 0 | D |
12 | CACNA1D | 3 | T | C | Val123Ala | 5.45 | 26.4 | 16.36 | high | 0.999 | P | 0.57 | high | 0.02 | D |
13 | CACNA1D | 3 | G | A | Gly1562Arg | 5.60 | 34 | 16.36 | high | 0.986 | P | 0.57 | high | 0 | D |
14 | CACNA1H | 16 | C | T | Pro277Ser | 48.37 | 24.4 | 0.001 | high | 0.971 | P | 0.001 | high | 0.03 | D |
15 | CACNA1H | 16 | A | G | Gln875Arg | 8.03 | 25.9 | 0.001 | high | 0.830 | P | 0.001 | high | 0 | D |
16 | CACNA1H | 16 | A | G | Thr615Pro | 10.45 | 25.3 | 0.001 | high | 0.766 | P | 0.001 | high | 0 | D |
17 | CACNA1H | 16 | C | T | Gln904Ter | 10.20 | 38 | 0.001 | high | n/a | n/a | 0.001 | n/a | 0 | D |
18 | CACNA1H | 16 | G | A | Trp482Ter | 13.54 | 36 | 0.001 | high | n/a | n/a | 0.001 | n/a | 0.17 | T |
19 | CLCN2 | 3 | C | G | Gly466Ala | 37.01 | 25.5 | 0.001 | high | 0.489 | P | 0.02 | high | 0 | D |
20 | CLCN2 | 3 | A | G | Phe252Ser | 17.33 | 28.3 | 0.001 | high | 0.997 | P | 0.02 | high | 0 | D |
21 | CTNNB1 | 3 | C | T | Gln123Ter | 7.87 | 37 | 16.39 | high | n/a | n/a | 0.239 | n/a | 0.01 | D |
All | cNGS-Identified Mutation Carrier | Cngs-Identified Mutation Non-Carrier | p Value (Mutation Carrier vs. Non-Carrier) | |
---|---|---|---|---|
Number | 75 | 21 | 54 | |
Female (%) | 43 (57.3%) | 14 (66.7%) | 29 (53.7%) | 0.436 |
Age (years) | 54.5 (10.6) | 53.5 (10.4) | 54.9 (10.7) | 0.603 |
BMI (kg/m2) | 26.2 (4.0) | 25.3 (3.4) | 26.5 (4.2) | 0.266 |
sBP (mmHg) | 152.0 (20.8) | 145.0 (19.9) | 154.6 (20.7) | 0.071 |
dBP (mmHg) | 90.8 (14.5) | 88.3 (17.4) | 91.8 (13.3) | 0.345 |
PRA (ng/mL per min)† | 0.83 (2.32) | 1.32 (4.07) | 0.64 (1.06) | 0.455 |
Plasma aldosterone (ng/dL)† | 49.8 (35.2) | 47.1 (29.9) | 50.8 (37.2) | 0.68 |
Log ARR† | 2.28 (0.83) | 2.33 (0.96) | 2.26 (0.79) | 0.742 |
Potassium (mmol/L)† | 3.6 (0.6) | 3.7 (0.6) | 3.5 (0.6) | 0.155 |
Serum creatinine (mg/dL) | 0.93 (0.36) | 0.85 (0.30) | 0.95 (0.38) | 0.279 |
Cystatin C (mg/L) | 0.84 (0.23) | 0.75 (0.25) | 0.87 (0.30) | 0.246 |
Microalbuminuria (g/day) | 0.06 (0.12) | 0.07 (0.13) | 0.05 (0.11) | 0.546 |
Tumor size (cm) | 2.09 (2.57) | 2.28 (2.98) | 2.02 (2.43) | 0.695 |
baPWV (cm/s) | 1722.0 (329.2) | 1647.5 (256.4) | 1765.2 (361.8) | 0.231 |
Clinical success (%) | 0.010 | |||
Complete | 33 (44%) | 15 (71.4%) | 18 (33.3%) | |
Absent | 16 (21.3%) | 3 (14.3%) | 13 (24.1%) | |
Partial | 26 (34.7%) | 3 (14.3%) | 23 (42.6%) | |
Biochemical success (%) | 0.440 | |||
Complete | 61 (81.3%) | 18 (85.7%) | 43 (79.6%) | |
Absent | 10 (13.3%) | 3 (14.3%) | 7 (13%) | |
Partial | 4 (5.3%) | 0 | 4 (7.4%) |
Model Fitting Criteria | Likelihood Ratio Tests | ||||
---|---|---|---|---|---|
AIC of Reduced Model | BIC of Reduced Model | −2 Log Likelihood of Reduced Model | Chi-Square | Sig. | |
Age(yr) | 165.545 | 216.530 | 121.545 | 1.825 | 0.402 |
BMI(kg/m2) | 164.742 | 215.727 | 120.742 | 1.022 | 0.600 |
SBP(mmHg) | 163.969 | 214.954 | 119.969 | 0.249 | 0.883 |
DBP(mmHg) | 167.660 | 218.645 | 123.660 | 3.940 | 0.139 |
Aldosterone(ng/dL) † | 167.252 | 218.237 | 123.252 | 3.532 | 0.171 |
PRA(ng/mL/h) † | 165.395 | 216.380 | 121.395 | 1.675 | 0.433 |
Potassium(mEq/L) † | 164.553 | 215.538 | 120.553 | 0.833 | 0.659 |
Cr (mg/dL) | 165.379 | 216.364 | 121.379 | 1.659 | 0.436 |
Tumor size (cm) | 168.261 | 219.246 | 124.261 | 4.541 | 0.103 |
cNGS-identified mutation (yes) | 172.646 | 223.631 | 128.646 | 8.926 | 0.012 |
Sex(Female) | 168.601 | 219.586 | 124.601 | 4.881 | 0.087 |
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Wu, C.-H.; Peng, K.-Y.; Hwang, D.-Y.; Lin, Y.-H.; Wu, V.-C.; Chueh, J.S. Novel Mutations Detection with Next-Generation Sequencing and Its Association with Clinical Outcome in Unilateral Primary Aldosteronism. Biomedicines 2021, 9, 1167. https://doi.org/10.3390/biomedicines9091167
Wu C-H, Peng K-Y, Hwang D-Y, Lin Y-H, Wu V-C, Chueh JS. Novel Mutations Detection with Next-Generation Sequencing and Its Association with Clinical Outcome in Unilateral Primary Aldosteronism. Biomedicines. 2021; 9(9):1167. https://doi.org/10.3390/biomedicines9091167
Chicago/Turabian StyleWu, Che-Hsiung, Kang-Yung Peng, Daw-Yang Hwang, Yen-Hung Lin, Vin-Cent Wu, and Jeff S. Chueh. 2021. "Novel Mutations Detection with Next-Generation Sequencing and Its Association with Clinical Outcome in Unilateral Primary Aldosteronism" Biomedicines 9, no. 9: 1167. https://doi.org/10.3390/biomedicines9091167