Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort: Report of 12 New Cases and Literature Review
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients
2.2. Genetic Tests and Data Analysis
2.3. Multiplex Ligation-Dependent Probe Amplification (MLPA)
2.4. Interferon Signature
3. Results
3.1. RNASEH2B Variants
3.2. TREX1 Variants
3.3. RNASEH2A Variants
3.4. RNASEH2C Variants
3.5. SAMHD1 Variants
3.6. ADAR1 Variants
3.7. IFIH1 variants
3.8. AGS Patients without Mutation in AGS-Related Genes
3.9. Interferon Signature
4. Discussion
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Patient | Gene | Variant | Amino Acidic Substitution | Number of Patients (Gender) | Annotation * | Onset ** | Clinical Score # | Clinical Phenotype | Epilepsy | GQ/IQ ° | Chilblains and/or Recurrent Fevers | Other |
---|---|---|---|---|---|---|---|---|---|---|---|---|
P1 | TREX1 | c.341G>A | p.R114H | 1 (Male) | Described [1] | Prenatal/neonatal | ≥12 | Spastic tetraparesis | Yes | Not evaluable | No | s- |
P2 | TREX1 | c.262 ins AG + c.290G>A | p.S88Kfs* + p.R97H | 1(Male) | Described [25] | Prenatal/neonatal | ≥12 | Spastic-dystonic tetraparesis | No | Not evaluable | No | Antiphospholipid syndrome, thyroiditis, cerebral ischemia |
P3 | TREX1 | c.150_151del | p.N51Gfs*50 | 1 (Male) | Described [1] | Prenatal/neonatal | ≥12 | Spastic tetraparesis | No | Not evaluable | Yes | Cardiomyopathy |
P4 | TREX1 | c.868_885del + c.341G>A | p.P290_A295del + p.R114H | 1(Male) | Described [1] | Prenatal/neonatal | ≥12 | Spastic-dystonic tetraparesis | Yes | Not evaluable | Yes | Cardiomyopathy, pulmonary hypertension, sensoryneural hearing loss |
P5 | RNASEH2A | c.322C>T + c.690C>A | p.R108W + p.F231L | 1(Female) | Described [1] | Prenatal/neonatal | ≥12 | Spastic-dystonic tetraparesis | No | Not evaluable | No | Celiac disease |
P6 | RNASEH2A | c.556C>T + c.69G>A | p.R186W + p.V23V | 1 (Male) | Described [26] | Prenatal/neonatal | ≥12 | Spastic tetraparesis | Yes | Not evaluable | No | - |
P7-P23 | RNASEH2B | c.529G>A | p.A177T | 17 (9 Males, 8 Females) | Described [1,21] | Infantile to later onset | 4 patients ≤ 6 2 patients 6–12 11 patients≥ 12 | Variable (Hemiparesis/Spastic diplegia/hypotonic-dystonic syndrome/Spastic-dystonic tetraparesis) | Yes (4 patients) No (13 patients) | Variable (from notevaluable to 90) | Yes/No | Variable neuroradiological features (brain calcification/no calcification/diffuse microcalcification/MRI normalization at follow up) |
P24-P30 | RNASEH2B | c.529G>A + c.488C>T | p.A177T + p.T163I | 7 (2 Males, 5 Females) | Described [1] | Prenatal to infantile | ≥12 | Spastic-dystonic tetraparesis | Yes (3 patients) No (4 patients) | Variable (from not evaluable to >50) | No | Variable (no other features to celiac disease) |
P31-P32† | RNASEH2B | c.529G>A + c.218G>T | p.A177T + p.W73L | 2 (1 Male, 1 Female) | Described [27] | Infantile | 6–12 (1 patient 11 1 patient 8) | Spastic-dystonic tetraparesis | No | 1 patient <501 patient not evaluable | Yes | Variable neuroradiological features (brain calcification/ no calcification) |
P33 | RNASEH2B | c.529G>A +c.Ex9_Ex11del | p.A177T + p.Ex9_Ex11del | 1 (Male) | Novel | Prenatal/neonatal | ≥12 | Spastic-dystonic tetraparesis | Yes | Not evaluable | Yes | - |
P34 | RNASEH2B | c.554T>G | p.V185G | 1 (Male) | Described [1] | Prenatal/neonatal | ≥12 | Spastic-dystonic tetraparesis | Yes | Not evaluable | Yes | - |
P35 | RNASEH2B | c.529G>A + c.635C>T | p.A177T + p.A212V | 1 (Female) | Novel | Infantile | ≥12 | Spastic-dystonic tetraparesis | No | Not evaluable | Yes | - |
P36 | RNASEH2B | c.529G>A + c.64+1G>A | p.A177T | 1 (Male) | Described [1] | Infantile | ≥12 | Spastic tetraparesis | Yes | Not evaluable | Yes | - |
P37 | RNASEH2C | c.115G>T + c.173-1G>C | p.D39Y | 1 (Male) | Described [1] | Infantile | ≥12 | Spastic-dystonic tetraparesis | No | Not evaluable | Yes | - |
P38-P39† | SAMHD1 | c.410A>G | p.D137G | 2 (1 Male, 1 Female) | Novel | Infantile | 1patient 6 1 patient ≥12 | Spastic paraparesis/spastic-dystonic tetraparesis | No | 1 patient 60 1 patient <50 | Yes | - |
P40 | SAMHD1 | c.1393C>T +c.1410+5G>C | p.Q465* | 1 (Female) | Novel | Infantile | ≥12 | Spastic-dystonic tetraparesis | No | <50 | Yes | - |
P41 | SAMHD1 | Ex12_Ex16del | p.Ex12_Ex16del | 1 (Male) | Described [28] | Infantile | ≥12 | Spastic-dystonic tetraparesis | Yes | <50 | No | Cerebral vasculitis, three intracranial aneurysms |
P42 | ADAR1 | c.577C>G + c.2608G>A | p.P193A + p.A870T | 1 (Male) | Described [1,29] | Infantile | ≥12 | Spastic-dystonic tetraparesis | No | Not evaluable | No | Striatal necrosis |
P43 | IFIH1 | c.1178A>T | p.D393V | 1 (Male) | Described [1,30] | Later onset | ≥12 | Spastic-dystonic tetraparesis | Yes | Not evaluable | No | - |
P44 | IFIH1 | c.2471G>A | p.R824K | 1 (Male) | Described [31] | Infantile | ≥12 | Spastic-dystonic tetraparesis | No | Not evaluable | No | - |
P45-46 | IFIH1 | c.2336G>A | p.R779H | 2 (2 Males) | Described [1] | Infantile | ≥12 | Spastic-dystonic tetraparesis | No | Not evaluable | Yes | - |
P47 | IFIH1 | c.2159G>A | p.R720Q | 1 (Male) | Described [1] | Infantile | ≥12 | Spastic tetraparesis | Yes | Not evaluable | Yes | |
P48 | IFIH1 | c.2561T>A | p.M854K | 1 (Male) | Novel | Later onset | <6 | Spastic paraparesis | Yes | 97 | No | Erythematous cheeks, lentiges, hyperkeratotic lesions, glaucoma, abnormal dentition, demyelinating sensory-motor polyneuropathy |
P49 | RNASET2 | c.397_399delAAG + c.145G > T | p.K133del +p.E49* | 1 (Male) | Described [32] | Infantile | ≥12 | Spastic-dystonic tetraparesis | No | Not evaluable | No | Cerebellar atrophy |
P50 | / | / | / | 1 (Male) | / | Infantile | ≥12 | Spastic-dystonic tetraparesis | No | < 50 | No | Hypopigmented lesions, thyroiditis |
P51 | / | / | / | 1 (Female) | / | Infantile | <6 | Spastic diplegia | Yes | <50 | Yes | Hypochromic lesions on trunk |
Gene | Mutation | Homozygous/Heterozygous % | MAF £ (ExAC) |
---|---|---|---|
TREX1 | p.S88Kfs* | 0/1 | NA |
p.R97H | 0/1 | T = 0.000008/1 | |
p.R114H | 1/1 | A = 0.0002/19 | |
p.N51Gfs*50 | 1/0 | NA | |
p.P290_A295del | 0/1 | - = 0.00007/8 | |
p.R169H | 0/1 | A = 0.0002/19 | |
RNASEH2A | p.R108W | 0/1 | A = 0.000008/1 |
p.F230L | 0/1 | A = 0.000008/1 | |
p.R186W | 0/1 | NA | |
p.V23V | 0/1 | A = 0.00002/3 | |
RNASEH2B | p.W73L | 0/2 | NA |
p.T163I | 0/7 | NA | |
p.A177T | 17/12 | A = 0.0013/158 | |
p.V185G | 1/0 | NA | |
p.A212V | 0/1 | NA | |
p.Ex9_Ex11del | 0/1 | NA | |
c.64+1G>A | 0/1 | NA | |
RNASEH2C | p.D39Y | 0/1 | NA |
c.173-1G>C | 0/1 | ||
SAMHD1 | p.D137G | 2/0 | T = 0.000008/1 |
p.Q465* | 0/1 | NA | |
c.1410+5G>C | 0/1 | NA | |
p.Ex12_Ex16del | 1/0 | NA | |
ADAR1 | p.P193A | 0/1 | C = 0.0021/260 |
p.A870T | 0/1 | NA | |
IFIH1 | p.D393V | 0/1 | C = 0.000008/1 |
p.R720Q | 0/1 | NA | |
p.R824K | 0/1 | NA | |
p.R779H | 0/2 | NA | |
p.M854K | 0/1 | NA | |
RNASET2 | p.K133del | 0/1 | - = 0.00002/2 |
p.E49* | 0/1 | NA |
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Garau, J.; Cavallera, V.; Valente, M.; Tonduti, D.; Sproviero, D.; Zucca, S.; Battaglia, D.; Battini, R.; Bertini, E.; Cappanera, S.; et al. Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort: Report of 12 New Cases and Literature Review. J. Clin. Med. 2019, 8, 750. https://doi.org/10.3390/jcm8050750
Garau J, Cavallera V, Valente M, Tonduti D, Sproviero D, Zucca S, Battaglia D, Battini R, Bertini E, Cappanera S, et al. Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort: Report of 12 New Cases and Literature Review. Journal of Clinical Medicine. 2019; 8(5):750. https://doi.org/10.3390/jcm8050750
Chicago/Turabian StyleGarau, Jessica, Vanessa Cavallera, Marialuisa Valente, Davide Tonduti, Daisy Sproviero, Susanna Zucca, Domenica Battaglia, Roberta Battini, Enrico Bertini, Silvia Cappanera, and et al. 2019. "Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort: Report of 12 New Cases and Literature Review" Journal of Clinical Medicine 8, no. 5: 750. https://doi.org/10.3390/jcm8050750
APA StyleGarau, J., Cavallera, V., Valente, M., Tonduti, D., Sproviero, D., Zucca, S., Battaglia, D., Battini, R., Bertini, E., Cappanera, S., Chiapparini, L., Crasà, C., Crichiutti, G., Dalla Giustina, E., D’Arrigo, S., De Giorgis, V., De Simone, M., Galli, J., La Piana, R., ... Cereda, C. (2019). Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort: Report of 12 New Cases and Literature Review. Journal of Clinical Medicine, 8(5), 750. https://doi.org/10.3390/jcm8050750