Genotype–Phenotype Correlation in Neurofibromatosis Type 1: Evidence for a Mild Phenotype Associated with Splicing Variants Leading to In-Frame Skipping of NF1 Exon 24 [19a]
Abstract
:Simple Summary
Abstract
1. Introduction
2. Patients and Methods
2.1. Individuals and Phenotypic Data
2.2. Comprehensive NF1 Molecular Analysis
2.3. Splicing Assessment for Twelve NF1 Variants at Seven Positions (c.3114-2, c.3114-1, c.3196, c.3197, c.3197+1, c.3197+2, c.3197+3), Which Might Be Associated with Exon 24 [19a] Skipping but Not Detected in the UAB Cohort
2.4. Effects of NF1 Exon 24 [19a] Skipping on 3D Structure of Neurofibromin
2.5. Assessment of Expression/Stability and Activity of Mouse Neurofibromin Lacking 28 Amino Acids Encoded by Exon 24 in Cells
2.6. Statistical Analysis
3. Results
3.1. Description of the Variants Leading to NF1 Exon 24 [19a] Skipping
3.2. Clinical Characterization of the Patient Cohort
3.3. Comparison of Clinical Features of the Studied Cohort with the Cohort of Individuals Heterozygous for NF1 p.Met992del, Cohorts of Individuals Carrying NF1 Missense Pathogenic Variants Affecting Codons 1809 and 844–848, and “Classic” NF1 Population
3.4. Assessment of NF1 Variants at c.3114-2, c.3114-1, c.3196, c.3197, c.3197+1, c.3197+2, c.3197+3, Which Potentially Lead to Exon 24 [19a] Skipping but Have Not Been Reported
3.5. 3D Structure Change of Neurofibromin Due to NF1 Exon 24 [19a] Skipping
3.6. Mutant Neurofibromin Levels and Ras Activity in HEK293 Cells
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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Variant (cDNA Level) | Number of Patients in the UAB Cohort | Confirmed by RNA-Based Testing (Number of RNA Tests) | 1000G | gnomAD | LOVD | ClinVar | HGMD | Evidence | Classification of Pathogenicity |
---|---|---|---|---|---|---|---|---|---|
c.3114-2A>G | 7 | Yes (5; this study and PMID: 24789688) | 0 | 1 (in 1435698) | 2 (Pathogenic/NA) | Present (Likely pathogenic) | Present (DM) | PVS1 (RNA) a + PS4_strong b | Pathogenic |
c.3114-1G>A | 4 | Yes (3; this study) | 0 | 0 | 0 | Present (Likely pathogenic) | 0 | PVS1 (RNA) + PS4_strong + PM2 e | Pathogenic |
c.3196A>G | 5 | Yes (3; this study) | 0 | 1 (in 1455704) | 0 | Present (VUS) | 0 | PVS1 (RNA) + PS4_strong | Pathogenic |
c.3197G>A | 2 | Yes (1; this study) | 0 | 0 | 4 (Pathogenic; including 1 de novo) | Present (Conflicting: Likely pathogenic/VUS) | Present (DM) | PVS1 (RNA) + PS4_moderate c + PM6 f | Pathogenic |
c.3197G>T | 2 | Yes (1; this study) | 0 | 0 | 0 | Present (VUS) | 0 | PVS1 (RNA) + PS4_supporting d + PM2 | Pathogenic |
c.3197+1G>A | 3 | Yes (5; this study and PMID: 10607834, 18546366) | 0 | 0 | 1 (Pathogenic; de novo) | Present (Pathogenic/Likely pathogenic) | Present (DM) | PVS1 (RNA) + PS4_strong + PM2 + PM6 | Pathogenic |
c.3197+1G>T | 1 | Yes (1; PMID: 18546366) | 0 | 0 | 3 (Pathogenic; including 1 de novo) | Present (Pathogenic) | Present (DM) | PVS1 (RNA) + PM2 + PM6 | Pathogenic |
c.3197+2T>C | 2 | Yes (1; this study) | 0 | 0 | 2 (Pathogenic) | Present (Pathogenic) | 0 | PVS1 (RNA) + PS4_suppoorting + PM2 | Pathogenic |
c.3197+3A>T | 14 | Yes (2; this study) | 0 | 0 | 0 | Present (VUS) | 0 | PVS1 (RNA) + PS4_strong + PP1_strong g + PM2 | Pathogenic |
NF1 Feature | N (%) | p Value (2-Tailed Fisher’s Exact Test) | |||||||
---|---|---|---|---|---|---|---|---|---|
Skipping Exon 24 [19a] | p.Met992del a | p.Arg1809 b | aa 844–848 c | Previously Reported NF1 Cohorts d | Skipping Exon 24 [19a] vs. p.Met992del | Skipping Exon 24 [19a] vs. p.Arg1809 | Skipping Exon 24 [19a] vs. aa 844–848 | Skipping Exon 24 [19a] vs. “Classic” NF1 | |
≥6 CALMs | 34/40 (85.0) | 165/182 (90.7) | 157/169 (92.9) | 130/157 (82.8) | 1537/1728 (89) | 0.2662 | 0.1211 | 0.8174 | 0.4415 |
Skinfold freckling | 23/38 (60.5) | 105/171 (61.4) | 95/161 (59) | 104/144 (72.2) | 1403/1667 (84.2) | 1 | 1 | 0.1699 | 0.0005 ** ↘ |
Lisch nodules | 0/23 (0) | 16/139 (11.5) | 12/120 (10) | 42/98 (42.9) | 729/1237 (58.9) | 0.1307 | 0.0768 | <0.0001 ** ↘ | <0.0001 ** ↘ |
Major external plexiform neurofibromas e | 0/18 (0) | 0/125 (0) | 0/105 (0) | 36/92 (39.1) | 120/648 (18.5) | 1 | 1 | 0.0006 ** ↘ | 0.0554 |
Cutaneous neurofibromas f | 0/8 (0) g | 0–1/57 (0–1.8) h | 0/57 (0) | 47/69 (68.1) | 656/723 (90.7) | 1 | 1 | 0.0003 ** ↘ | <0.0001 ** ↘ |
Subcutaneous neurofibromas f | 0/8 (0) | 0–3/36 (0–8.3) h | 0–5/57 (0–8.8) h | 33/65 (50.8) | 297/515 (57.7) | 1 | 1 | 0.0068 * ↘ | 0.0011 ** ↘ |
Symptomatic spinal neurofibromas | 0/33 (0) | 1/165 (0.6) | 0/76 (0) | 13/127 (10.2) | 36/2058 (1.8) | 1 | 1 | 0.0719 | 1 |
Symptomatic OPGs i | 0/37 (0) | 0/170 (0) | 0/139 (0) | 12/136 (8.8) | 64/1650 (3.9) | 1 | 1 | 0.0721 | 0.3981 |
Skeletal abnormalities | 4/36 (11.1) | 30/172 (17.4) | 21/126 (16.7) | 48/144 (33.3) | 144/948 (15.2) | 0.4609 | 0.6014 | 0.0076 * ↘ | 0.6386 |
Scoliosis f | 2/36 (5.6) | 7/57 (12.3) | 6/48 (12.5) | 20/64 (31.3) | 51/236 (21.6) | 0.4742 | 0.4566 | 0.0025 * ↘ | 0.0229 ↘ |
Cognitive impairment, developmental delay, and/or learning disabilities | 13/39 (33.3) | 58/176 (33) | 80/159 (50.3) | 56/138 (40.6) | 190/424 (44.8) | 1 | 0.0731 | 0.461 | 0.1811 |
Noonan-like features j | 1/35 (2.9) | 19/166 (11.5) | 46/148 (31.1) | 10/134 (7.5) | 57/1683 (3.4) | 0.2099 | 0.0002 ** ↘ | 0.4629 | 1 |
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Chen, Y.; Fu, Y.; Koczkowska, M.; Callens, T.; Gomes, A.; Liu, J.; Bradley, W.; Brown, B.; Shaw, B.; D’Agostino, D.; et al. Genotype–Phenotype Correlation in Neurofibromatosis Type 1: Evidence for a Mild Phenotype Associated with Splicing Variants Leading to In-Frame Skipping of NF1 Exon 24 [19a]. Cancers 2024, 16, 2406. https://doi.org/10.3390/cancers16132406
Chen Y, Fu Y, Koczkowska M, Callens T, Gomes A, Liu J, Bradley W, Brown B, Shaw B, D’Agostino D, et al. Genotype–Phenotype Correlation in Neurofibromatosis Type 1: Evidence for a Mild Phenotype Associated with Splicing Variants Leading to In-Frame Skipping of NF1 Exon 24 [19a]. Cancers. 2024; 16(13):2406. https://doi.org/10.3390/cancers16132406
Chicago/Turabian StyleChen, Yunjia, Yulong Fu, Magdalena Koczkowska, Tom Callens, Alicia Gomes, Jian Liu, William Bradley, Bryce Brown, Brandon Shaw, Daniela D’Agostino, and et al. 2024. "Genotype–Phenotype Correlation in Neurofibromatosis Type 1: Evidence for a Mild Phenotype Associated with Splicing Variants Leading to In-Frame Skipping of NF1 Exon 24 [19a]" Cancers 16, no. 13: 2406. https://doi.org/10.3390/cancers16132406
APA StyleChen, Y., Fu, Y., Koczkowska, M., Callens, T., Gomes, A., Liu, J., Bradley, W., Brown, B., Shaw, B., D’Agostino, D., Fu, C., & Wallis, D. (2024). Genotype–Phenotype Correlation in Neurofibromatosis Type 1: Evidence for a Mild Phenotype Associated with Splicing Variants Leading to In-Frame Skipping of NF1 Exon 24 [19a]. Cancers, 16(13), 2406. https://doi.org/10.3390/cancers16132406