Moyamoya Vasculopathy in Neurofibromatosis Type 1 Pediatric Patients: The Role of Rare Variants of RNF213
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Patients and Controls
2.2. DNA Extraction
2.3. Next-Generation Sequencing (NGS)
2.4. Multiplex Ligation-Dependent Probe Amplification (MLPA)
2.5. RNA Extraction, RT-PCR and Sequencing of NF1 Gene
2.6. Statistical Analysis
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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Overall (n = 92) | MMS (n = 20) | MMD (n = 25) | NF1 (n = 47) | p-Value | p-Value Pairwise Comparisons | ||
---|---|---|---|---|---|---|---|
Sex | Females | 48 (52.2%) | 12 (60.0%) | 15 (60.0%) | 21 (44.7%) | 0.34 ^ | |
Males | 44 (47.8%) | 8 (40.0%) | 10 (40.0%) | 26 (55.3%) | |||
Age | years | 9.3 ± 5.02 | 11.2 ± 4.84 | 7.4 ± 3.33 | 9.5 (±5.55) | 0.036 ^^* | MMD/NF1: 0.29 MMD/MMS: 0.032 * NF1/MMS: 0.56 |
Diagnosis age | years | 5.5 ± 2.10 | 6.7 ± 1.93 | 4.6 ± 1.04 | 5.4 (±2.38) | 0.003 ^^* | MMD/NF1: 0.18 MMD/MMS: 0.002 * NF1/MMS: 0.10 |
Familial cases | 6 | 2 | - | 4 |
Patient | Sex | Genotype (cDNA and Protein Change) | ACMG/ClinVar/LOVD Prediction | gnomAD/ DGV Frequency | Biogear Frequency |
---|---|---|---|---|---|
MMS-1 | F | NF1 c.2536G>C (p.Ala846Pro) RNF213 c.4907C>T (p.Thr1636Met) | P/P/P VUS/-/- | - 2.6 × 10−5 | - - |
MMS-2 | M | NF1 c.7285C>T (p.Arg2429 *) RNF213 WT | P/P/P | - | - |
MMS-3 | F | NF1 c.4381delA (p.Ile1461 *) RNF213 WT | LP/-/- | - | - |
MMS-4 | F | NF1 c.5483A>T (p.Asp1849Val) RNF213 WT | P/C/VUS | - | - |
MMS-5 | F | NF1 c.4276_4282delinsAG (p.Gln1447Serfs * 18) RNF213 WT | LP/-/- | - | - |
MMS-6 | F | NF1 c.2131delC (p.Arg711Alafs * 37) RNF213 c.10403C>T (p.Ala3468Val) | P/P/- VUS/-/- | - 1.3 × 10−4 | - 7 × 10−4 |
MMS7 | F | NF1 c.3496+1G>A RNF213WT | P/P/- | - | - |
MMS-8 | F | NF1 c.2909delA (p.Asn970Thrfs * 3) RNF213 WT | LP/-/- | - | - |
MMS-9 | M | NF1 c.1399dupA (p.Thr467Hisfs * 3) RNF213 WT | P/P/- | - | - |
MMS-10 | M | NF1 c.5725T>C (p.Cys1930Arg) RNF213 WT | P/C/P | - | - |
MMS-11 | F | NF1 c.1642-8A>G RNF213 WT | P/P/- | - | - |
MMS-12 | M | NF1c.7553_7575del (exon 51 del) RNF213 WT | LP/-/- | - | - |
MMS-13 | F | NF1 c5547_5943del (exons 38–39 del) RNF213 WT | P/P/- - | Very rare in DGV - | - |
MMS-14 | F | NF1 WT ^ RNF213 c.3721G>A (p.Ala1241Thr) | - VUS/-/- | - 1.9 × 10−5 | - 3 × 10−4 |
MMS-15 | M | NF1 c.6179T>G (p.Leu2081 *) RNF213 WT | LP/-/- | - | - |
MMS-16 | F | NF1 c.2356C>A (p.Gln786Lys) RNF213 WT | LP/VUS/- | - | - |
MMS-17 | M | NF1 c.610dupC (p.Leu204Profs * 12) RNF213 WT | P/LP/- | - | - |
MMS-18 ‡ | M | NF1 c.586+4dupA RNF213 WT | VUS/VUS/- | - | - |
MMS-19 | F | NF1 c.5010dupG (p.Tyr1671Valfs * 3) RNF213 WT | LP/-/- | - | - |
MMS-20 ‡ | M | NF1 c.5767dupC (p.Ile1923Profs * 20) RNF213 WT | P/-/- | - | - |
Patient | Sex | Genotype (cDNA and Protein Change) | ACMG/ClinVar/LOVD Prediction | gnomAD Frequency | Biogear Frequency |
---|---|---|---|---|---|
NF-1 | M | NF1 c.1885G>A (p.Gly629Arg) RNF213 WT | P/P/P | - | - |
NF-2 | M | NF1 c.5242C>T (p.Arg1748 *) RNF213 WT | P/P/P | - | - |
NF-3 | M | NF1 c.2970_2972del (p.Met992del) RNF213 WT | P/P/P | 8.2 × 10−6 | - |
NF-4 | M | NF1 c.545del (p.Tyr182Leufs * 9) RNF213 WT | LP/-/- | - | - |
NF-5 | M | NF1 c.493del (p.Thr165Leufs * 13) RNF213 WT | LP/-/- | - | - |
NF-6 | M | NF1 c.1544_1545del (p.Gly515Alafs * 42) RNF213 WT | LP/-/- | - | - |
NF-7 | M | NF1 c.973_974del (p.Val325Glnfs * 4) RNF213 WT | LP/-/- | - | - |
NF-8 | F | NF1 c.360dup (p.Leu121Serfs * 6) RNF213 WT | LP/-/- | - | - |
NF-9 | F | NF1 c.1144dup (p.Ser382Phefs * 14) RNF213 WT | LP/-/- | - | - |
NF-10 | F | NF1 c.5870del (p.Leu1957Argfs * 2) RNF213 WT | LP/-/- | - | - |
NF-11 | F | NF1 c.6391_6394del (p.Ser2131 *) RNF213 WT | LP/-/- | - | - |
NF-12 ‡ | M | NF1 c.850del (p.Ile284Tyrfs * 11) RNF213 WT | LP/-/- | - | - |
NF-13 ‡ | M | NF1 c.656del (p.Ala219Aspfs * 6) RNF213 WT | LP/-/- | - | - |
NF-14 | M | NF1 c.5401C>T (p.Gln1801 *) RNF213 WT | P/P/P | - | - |
NF-15 | F | NF1 c.229A>T (p.Lys77 *) RNF213 WT | LP/-/- | - | - |
NF-16 | M | NF1 c.3562C>T (p.Gln1188 *) RNF213 WT | P/P/P | - | - |
NF-17 | F | NF1 c.2033dup (p.Ile679Aspfs * 21) RNF213 WT | P/P/P | - | - |
NF-18 | M | NF1 c.3114-2A>G RNF213 WT | P/LP/P | - | - |
NF-19 | M | NF1 c.1381C>T (p.Arg461 *) RNF213 WT | P/P/P | - | - |
NF-20 ‡ | F | NF1 c.354_356delinsG (p.Cys118Trpfs * 8) RNF213 WT | LP/-/- | - | - |
NF-21 | M | NF1 c.3975-2A>G RNF213 WT | P/P/P | - | - |
NF-22 | F | NF1 c.5546G>A (p.Arg1849Gln) RNF213 WT | P/P/P | - | - |
NF-23 | F | NF1 c.4537C>T (p.Arg1513 *) RNF213 WT | P/C/P | 6 × 10−6 | - |
NF-24 | F | NF1 c.574C>T (p.Arg192 *) RNF213 WT | P/C/P | 1 × 10−5 | - |
NF-25 | M | NF1 c.7259-1_7259del (p.Ala2420Valfs * 15) RNF213 WT | LP/-/- | - | - |
NF-26 | F | NF1 c.2511G>A (p.Trp837 *) RNF213 WT | P/P/P | - | - |
NF-27 | F | NF1 c.3826C>T (p.Arg1276 *) RNF213 WT | P/P/P | - | - |
NF-28 | M | NF1 c.2409+1G>T RNF213 WT | P/P/P | - | - |
NF-29 | M | NF1 c.6401_6402del (p.Glu2134Valfs * 13) RNF213 WT | LP/-/- | - | - |
NF-30 | M | NF1 c.1246C>T (p.Arg416 *) RNF213 WT | P/P/P | 8 × 10−6 | - |
NF-31 | M | NF1 c.2540T>C (p.Leu847Pro) RNF213 WT | P/C/P | - | - |
NF-32 ‡ | F | NF1 c.3708+1G>T RNF213 WT | P/LP/P | - | - |
NF-33 | F | NF1 c.4206del (p.Ala1403Glnfs * 4) RNF213 WT | LP/-/- | - | - |
NF-34 | M | NF1 c.983_984del (p.Cys328 *) RNF213 WT | P/P/P | - | - |
NF-35 | M | NF1 c.516delT (p.Asp173Metfs * 5) RNF213 WT | LP/-/- | - | - |
NF-36 | M | NF1 c.2540T>C (p.Leu847Pro) RNF213 WT | P/C/P | - | - |
NF-37 | F | NF1 c.2456del (p.His819Leufs * 2) RNF213 WT | LP/-/- | - | |
NF-38 | F | NF1 c.6792C>A (p.Tyr2264 *) RNF213 WT | P/P/P | - | - |
NF-39 | M | NF1 c.1318C>T (p.Arg440 *) RNF213 WT | P/P/P | - | 1 × 10−4 |
NF-40 | M | NF1 c.7417_7425delinsAAGGT(Trp2473Lysfs * 28) RNF213 WT | LP/-/- | - | - |
NF-41 | F | NF1 c.2252-2A>G RNF213 WT | P/C/P | - | - |
NF-42 | F | NF1 c.204+1G>T RNF213 WT | P/P/P | 6 × 10−6 | - |
NF-43 | F | NF1 c.3445A>G (p.Met1149Val) RNF213 WT | P/C/P | 6 × 10−6 | - |
NF-44 | F | NF1 c.1466A>G (p.Tyr489Cys) RNF213 WT | P/P/P | 6 × 10−6 | - |
NF-45 | M | NF1 c.3827G>A (p.Arg1276Gln) RNF213 c.5162C>T (p.Pro1721Leu) | P/P/P VUS/-/- | 1 × 10−5 1 × 10−3 | - 2.7 × 10−3 |
NF-46 | F | NF1 c.5543T>G (p.Leu1848 *) RNF213 WT | P/P/P | - | - |
NF-47 | M | NF1 c.654+1G>C RNF213 WT | LP/-/P | - | - |
Patient | Sex | RNF213 Genotype | Protein Domain | ACMG/ClinVar/LOVD Prediction | gnomAD Frequency | Biogear Frequency |
---|---|---|---|---|---|---|
MMD-1 | F | c.5546T>G (pMet1849Arg) | N-term | VUS/-/- | - | - |
MMD-2 † | F | c.15062C>T (p.Ala5021Val) | C-term | VUS/B/- | 1.5 × 10−4 | - |
MMD-3 ‡ | M | c.10443G>A (p.Ala3481=) | B/-/- | - | 7 × 10−4 | |
MMD-4 | F | c.4146T>G (p.Thr1382=) | B/B/- | 8 × 10−3 | 5 × 10−3 | |
MMD-5 | M | WT | - | |||
MMD-6 | M | c.12050G>C (p.Cys4017Ser) | RF | VUS/-/- | - | - |
MMD-7 | F | c.5162C>T (p.Pro1721Leu) | N-term | VUS/VUS/- | 1 × 10−3 | 1 × 10−3 |
MMD-8 | F | WT | - | |||
MMD-9 | F | WT | - | |||
MMD-10 | M | WT | - | |||
MMD-11 | M | c.12103T>C (p.Cys4035Arg) | RF | VUS/-/- | - | - |
MMD-12 | M | WT | - | |||
MMD-13 | F | WT | - | |||
MMD-14 | F | c.9952A>G (p.Ile3318Val) | N-term | B/B/- | 1 × 10−3 | 1 × 10−2 |
MMD-15 | F | c.2063C>T (p.Thr688Met) | N-term | B/B/- | 1 × 10−3 | 3 × 10−4 |
MMD-16 | F | c.3496A>G (p.Asn1166Asp) | N-term | VUS/-/- | - | - |
MMD-17 | M | WT | - | |||
MMD-18 | F | WT | - | |||
MMD-19 | M | c.6042C>T (p.Asn2014=) c.15467G>A (p.Trp5156 *) | - C-term | B/B/- LP/-/- | 1 × 10−3 - | 3 × 10−3 - |
MMD-20 | F | c.14780G>A (p.Arg4927Gln) | C-term | VUS/-/- | 5 × 10−5 | - |
MMD-21 | F | WT | - | |||
MMD-22 | F | WT | - | |||
MMD-23 | M | WT | - | |||
MMD-24 | F | c.6551A>G (p.Gln2184Arg) | N-term | B/LB/- | 2 × 10−3 | - |
MMD-25 | M | c.13195G>A (p.Ala4399Thr) | C-term | B/P/- | 8 × 10−3 | 1 × 10−3 |
Carrier Frequency | IRR (95%CI); p-Value | |||||
---|---|---|---|---|---|---|
Domain | MMS (n = 20) | MMD (n = 25) | Biogear (n = 2504) | gnomAD (n = 141,456) | MMS | MMD |
N-term | 3 (15%) | 3 (12%) | 282 (11%) | NA | 1.33 (0.273–3.932); p = 0.58 * NA ** | 1.07 (0.22–3.15); p = 0.85 * NA ** |
RING finger | 0 | 2 (8%) | 8 (0.3%) | 227 (0.1%) | 0.00 (0.00–73.05); p = 0.80 * 0.00 (0.00–115.88); p = 0.86 ** | 25.04(2.59–125.47); p = 0.004 * 49.85 (6.00–182.17); p < 0.001 ** |
C-term | 0 | 4 (16%) | 61 (2.3%) | 1373 (0.9%) | 0.00 (0.00–7.80); p = 0.49 * 0.00 (0.00–19.03); p = 0.66 ** | 6.57(1.73–17.69); p = 0.004 * 16.48 (4.49–42.30); p < 0.001 ** |
RING finger + C-term | 0 | 6 (24%) | 69 (2.7%) | 1600 (1%) | 0.00 (0.00–6.88); p = 0.46 * 0.00 (0.00–19.03); p = 0.66 ** | 8.71(3.09–19.94); p < 0.001 * 21.22 (7.78–46.29); p < 0.001 ** |
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Ognibene, M.; Scala, M.; Iacomino, M.; Schiavetti, I.; Madia, F.; Traverso, M.; Guerrisi, S.; Di Duca, M.; Caroli, F.; Baldassari, S.; et al. Moyamoya Vasculopathy in Neurofibromatosis Type 1 Pediatric Patients: The Role of Rare Variants of RNF213. Cancers 2023, 15, 1916. https://doi.org/10.3390/cancers15061916
Ognibene M, Scala M, Iacomino M, Schiavetti I, Madia F, Traverso M, Guerrisi S, Di Duca M, Caroli F, Baldassari S, et al. Moyamoya Vasculopathy in Neurofibromatosis Type 1 Pediatric Patients: The Role of Rare Variants of RNF213. Cancers. 2023; 15(6):1916. https://doi.org/10.3390/cancers15061916
Chicago/Turabian StyleOgnibene, Marzia, Marcello Scala, Michele Iacomino, Irene Schiavetti, Francesca Madia, Monica Traverso, Sara Guerrisi, Marco Di Duca, Francesco Caroli, Simona Baldassari, and et al. 2023. "Moyamoya Vasculopathy in Neurofibromatosis Type 1 Pediatric Patients: The Role of Rare Variants of RNF213" Cancers 15, no. 6: 1916. https://doi.org/10.3390/cancers15061916