Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patient Cohort
2.2. X Inactivation
2.3. Targeted Next-Generation Sequencing
2.4. Variant Segregation and Additional Analysis
3. Results
3.1. Targeted Next-Generation Sequencing
3.2. Segregation Analysis and Genotype-Phenotype Correlation
3.2.1. Pathogenic/Likely Pathogenic Variants
Family ID0707
Family ID1122
Family ID1208
3.2.2. Variants of Unknown Significance
Family ID0216
Family ID1128
Family ID1402
Family ID1405
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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X Linked | Siblings | |||
---|---|---|---|---|
Total | n = 47 | n = 14 | ||
Age range | 2–63 | 2–24 | ||
0–10 | 26 | 55.32% | 9 | 64.29% |
10–20 | 10 | 21.28% | 4 | 28.57% |
>20 | 11 | 23.40% | 1 | 7.14% |
Intellectual disability | ||||
Mild/Borderline | 16 | 34.04% | 5 | 35.71% |
Moderate | 6 | 12.77% | 1 | 7.14% |
Severe | 3 | 6.38% | 1 | 7.14% |
Profound | 2 | 4.26% | 0 | |
Unknown | 20 | 42.55% | 7 | 50% |
Comorbidity | ||||
Macrocephaly | 1 | 2.13% | 0 | |
Microcephaly | 1 | 2.13% | 1 | 7.14% |
Autism Spectrum Disorder | 14 | 29.79% | 4 | 28.57% |
Hypotonia | 1 | 2.13% | 0 | |
Epilepsy | 7 | 14.89% | 0 | |
Behavioural disturbances | 5 | 10.64% | 2 | 14.29% |
Previous studies | ||||
Karyotype | 47 | 100% | 14 | 100% |
Fragile-X | 47 | 100% | 14 | 100% |
MLPA-X | 42 | 89.36% | 14 | 100% |
array CGH | 15 | 31.91% | 14 | 100% |
Patient ID | Gene | Variant | Inheritance 1 | Family History | GnomAD Allele Freq males | dbSNP | ClinVar | CADD 2 | InterVar 3 | InterVar (Manually Adjusted) |
---|---|---|---|---|---|---|---|---|---|---|
Pathogenic/likely pathogenic variants | ||||||||||
ID0707 | PHF8 | NM_001184896.1: c.252C>A; p.Tyr84* | Maternal (97.04%) | Sib-pair | 36 | Pathogenic (PVS1, PM2, PP3) | Pathogenic (PVS1, PM2, PP3) | |||
ID1204 | UPF3B | NM_080632.2: c.371-1G>C | Maternal (80.49%) | Sib-pair | Pathogenic (PVS1, PM2, PP3) | |||||
ID1122 | SLC6A8 | NM_005629.3: c.1390_1392del GAT; p.Asp464del | Maternal (79.37%) | X-linked | Likely Pathogenic (PVS1, PM2) | Pathogenic (PS3, PM2, PM4, PP1, PP3) | ||||
ID1208 | IQSEC2 | NM_001111125.2: c.128G>C; p.Arg43Pro | Maternal (53.7%) | X-linked | 26.2 | VUS (PM2) | Likely Pathogenic (PM2, PP1, PP2, PP3, PP4) | |||
Variants of unknown significance | ||||||||||
ID0216 | SLC9A6 | NM_001042537.1: c.316A>G; p.Met106Val | Maternal (57.09%) | X-linked | 23.1 | VUS (PM1, PM2, BP1) | VUS (PM1, PM2, PP1, BP1) | |||
ID0919 | UPF3B | NM_080632.2: c.1118G>A; p.Arg373His | Maternal (uninformative) | X-linked | 2/66856 | rs146785878 | VUS | 26.7 | VUS (PM2, PP3) | |
ID1010 | DLG3 | NM_021120.3: c.1424C>T; p.Ser475Leu | Maternal (91.97%) | Sib-pair | 1/75937 | rs953325312 | 31 | VUS (PM1, PM2, BP1) | ||
ID1011 | NHS | NM_198270.3: c.1270A>G; p.Arg424Gly | Maternal (uninformative) | X-linked | 23.7 | VUS (PM2, BP1) | ||||
ID1125 | FMR1 | NM_002024.5: c.1816C>T; p.Arg606Cys | Maternal (83.18%) | X-linked | 1/67871 | rs782778170 | 34 | VUS (PM1, PM2) | ||
ID1128 | HUWE1 | NM_031407.6: c.1125G>T; p.Met375Ile | Maternal (86.55%) | Sib-pair | 0/41548 | rs1043071474 | 22.6 | VUS (PM1, PM2) | VUS (PM1, PM2) | |
ID1205 | CASK | NM_003688.3: c.490G>A; p.Gly164Arg | Maternal (74.26%) | X-linked | 32 | VUS (PM1, PM2, PP3) | ||||
ID1206 | HUWE1 | NM_031407.6: c.12209C>G; p.Ser4070Cys | Maternal (97.31%) | Sib-pair | 24 | VUS (PM1, PM2) | ||||
ID1304 | CCDC22 | NM_014008.4: c.1388C>G; p.Ala463Gly | Maternal (54.33%) | X-linked | 1/73246 | rs782691732 | 26.9 | VUS (PM2) | ||
ID1307 | PRPS1 | NM_002764.3: c.611G>A; p.Arg204His | Maternal (uninformative) | X-linked | rs1169615098 | 24 | VUS (PM1, PM2, PP2) | |||
ID1402 | SYN1 | NM_006950.3: c.796G>A; p.Val266Met | Maternal (69.45%) | X-linked | rs1327735600 | 26.4 | VUS (PM1, PM2) | VUS (PM1, PM2, PP3) | ||
ID1405 | MED12 | NM_005120.2: c.5009C>T; p.Ser1670Phe | Maternal (95.36%) | X-linked | 33 | VUS (PM2) | VUS (PM2, PP1, PP3) | |||
Benign/likely benign variants | ||||||||||
ID1208 | MAOA | NM_000240.3: c.617G>A; p.Arg206Gln | Maternal (53.7%) | X-linked | rs1218703391 | 31 | VUS (PM1, PM2, PP3) | Likely benign (PM1, PM2, PP3, BS2, BP5) |
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Ibarluzea, N.; de la Hoz, A.B.; Villate, O.; Llano, I.; Ocio, I.; Martí, I.; Guitart, M.; Gabau, E.; Andrade, F.; Gener, B.; et al. Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability. Genes 2020, 11, 51. https://doi.org/10.3390/genes11010051
Ibarluzea N, de la Hoz AB, Villate O, Llano I, Ocio I, Martí I, Guitart M, Gabau E, Andrade F, Gener B, et al. Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability. Genes. 2020; 11(1):51. https://doi.org/10.3390/genes11010051
Chicago/Turabian StyleIbarluzea, Nekane, Ana Belén de la Hoz, Olatz Villate, Isabel Llano, Intzane Ocio, Itxaso Martí, Miriam Guitart, Elisabeth Gabau, Fernando Andrade, Blanca Gener, and et al. 2020. "Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability" Genes 11, no. 1: 51. https://doi.org/10.3390/genes11010051
APA StyleIbarluzea, N., de la Hoz, A. B., Villate, O., Llano, I., Ocio, I., Martí, I., Guitart, M., Gabau, E., Andrade, F., Gener, B., & Tejada, M.-I. (2020). Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability. Genes, 11(1), 51. https://doi.org/10.3390/genes11010051