Preimplantation Genetic Diagnosis of Neurodegenerative Diseases: Review of Methodologies and Report of Our Experience as a Regional Reference Laboratory
Abstract
:1. Introduction
1.1. Overview of Preimplantation Genetic Diagnosis
1.2. Current Status of PGD in Neurodegenerative Diseases
2. Materials and Methods
Genoty** Strategies Adopted in Our Laboratory
3. Results
3.1. Overall Outcomes
3.2. Example for ADO: The Index Family of FAP
4. Discussion
4.1. ADO in Our FAP PGD Case and Clinical Relevance
4.2. Ethical Aspects
4.3. Concurrent PGD/PGS
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Mutation Type | Disease (Gene) Examples | Genoty** Method | PGD Method |
---|---|---|---|
Inversion | Rare in neurodegenerative disorders | • I-PCR • Long-distance PCR • Southern blotting | • Linkage analysis |
Point mutations | Common in neurodegenerative disorders, e.g., ALS (FUS), FAP (TTR) | • Direct DNA sequencing • DHPLC • TTGE | • ARMS-qPCR • Linkage analysis • Mini-sequencing |
Small deletion/insertion (<1 exon) | Less common in neurodegenerative disorders, e.g., SMA (SMN1, SMN2) | • MLPA • Direct DNA sequencing | • ARMS-qPCR • Linkage analysis • Mini-sequencing • MARSALA |
Large duplication (≥1 exon) | Charcot–Marie–Tooth 1A (PMP22) | • MLPA • High resolution aCGH | • Linkage analysis |
Trinucleotide expansion | Very common in neurodegenerative disorders, e.g., Huntington’s disease (HTT), many subtypes of spinocerebellar ataxia (ATXN1, MJD1/ATXN3/SCA3), Poly Q diseases (ATN1, AR) | • Southern blotting • PCR followed by capillary electrophoresis (if CAG repeat number less than 100) | • Linkage analysis • Nested PCR followed by capillary electrophoresis (if CAG repeat number less than 100) |
Disease | PGD Method | Strategy | Cycles | Pregnancy Rate Per Oocyte Retrieval | Pregnancy Rate Per Embryo Transfer | Notation | Reference |
---|---|---|---|---|---|---|---|
Triplet repeat expansion | |||||||
Huntington’s disease | Single-cell PCR | Direct diagnosis | 9 | 1/153 | 1/13 | Sermon et al. [9] | |
Huntington’s disease | Multiple-cell PCR | Direct diagnosis | 15 | NA | NA | Nondisclosure testing a | Stern et al. [10] |
Huntington’s disease | Single-cell PCR | Exclusion testing | 7 | 1/67 | 1/6 | Sermon et al. [11] | |
Huntington’s disease | Single-cell WGA followed by PCR | Direct diagnosis | 1 | 1/15 | 1/2 | Chow et al. [12] | |
Huntington’s disease (and P450 oxidoreductase deficiency) | Single-cell PCR or two-cell PCR | Direct diagnosis | 2 | 0/18 | 0/2 | Alberola et al. [13] | |
Huntington’s disease | Single-cell PCR | Direct diagnosis or exclusion testing | 7 | NA | 2/10 | Peciña et al. [14] | |
Huntington’s disease | Single-cell PCR | Direct diagnosis or exclusion testing | 434 started; 389 continued to oocyte retrieval | 105/5218 | 105/511 | Van Rij et al. [15] | |
Huntington’s disease | Direct diagnosis and Linkage analysis | 1 | 1/16 | 1/1 | Perminov et al. [16] | ||
SCA2 | Single-cell PCR | Direct diagnosis | 2 | 2/36 | 2/4 | Moutou et al. [17] | |
SCA3 | Single-cell PCR | Direct diagnosis | 1 | 1/10 | 1/2 | Drüsedau et al. [18] | |
Huntington’s disease (and myotonic dystrophy, fragile X syndrome) | Two-cell PCR | Direct diagnosis | NA | NA | NA | No implantation data | Sermon et al. [19] |
Gene dosage or rearrangement | |||||||
Charcot–Marie–Tooth 1A | Single-cell PCR or two-cell PCR | Linkage analysis | 2 | 1/18 | 1/2 | Löfgren et al. [20] | |
Charcot–Marie–Tooth 1A | Two-cell PCR | Direct diagnosis | 13 | 3/138 | 3/11 | De Vos et al. [21] | |
Charcot–Marie–Tooth 1A | Single-cell PCR or two-cell PCR | Direct diagnosis | 6 | 4/117 | 4/13 | Lee et al. [22] | |
Charcot–Marie–Tooth 1A | Single-cell WGA followed by NGS | Direct diagnosis | 1 | NA | NA | No implantation data | Gui et al. [23] |
SMA 1 | Single-cell PCR or two-cell PCR | Direct diagnosis | 3 | NA | 2/7 | Fallon et al. [24] | |
SMA | Single-cell PCR | Direct diagnosis | 5 | 6/62 | 6/9 | Daniels et al. [25] | |
SMA | MARSALA | Direct diagnosis | 2 | NA | 1/1 | Ren et al. [26] | |
Point mutation or small insertion/deletion | |||||||
Charcot–Marie–Tooth X | Single-cell PCR or two-cell PCR | Direct diagnosis | 1 | 1/12 | 1/2 | Iacobelli et al. [27] | |
Charcot–Marie–Tooth X | Single-cell WGA followed by PCR | Linkage analysis | 2 | 1/10 | 1/2 | Borgulová et al. [28] | |
Charcot–Marie–Tooth 2F | Single-cell PCR or two-cell PCR | Direct diagnosis | 1 | 2/11 | 2/4 | Lee et al. [22] | |
Gerstmann-Straussler- Scheinker disease | Polar body PCR | Direct diagnosis | NA | 2/14 | 2/2 | Uflacker et al. [29] | |
FAP | Single-cell PCR | Direct diagnosis | 10 | 3/93 | 3/25 | Carvalho et al. [30] | |
FAP | Two-cell PCR | Direct diagnosis | 1 | 2/10 | 2/3 | Almeida et al. [31] |
Case No. | Maternal Age | Disease | Inheritance | Gene | Mutation Type | Diagnostic Methodology | No. of Oocyte Retrieval Cycle | Embryos Diagnosed | Diagnostic Result (Unaffected/Affected) | No. of Embryo Transfer Cycle (No. of Embryos Transferred) | Pregnancy Outcome |
---|---|---|---|---|---|---|---|---|---|---|---|
1 | 30–34 | SCA3 | AD | MJD1 | Trinucleotide expansion | Linkage analysis | 1 | 6 | 2/4 | 1 (2) | No implantation |
2 | 40–44 | SCA3 | AD | MJD1 | Trinucleotide expansion | Linkage analysis | 1 | 2 | 1/1 | 1 (1) | No implantation |
3 | 25–29 | SCA6 | AD | CACNA1A | Trinucleotide expansion | Linkage analysis | 2 | 12 | 6/6 | 2 (6) | No implantation |
4 | 35–39 | Charcot–Marie–Tooth 2E | AD | NEFL | Point mutation c.23C>G (p.P8R) | ARMS-qPCR + Linkage analysis | 2 | 13 | 8/5 | 2 (8) | No implantation |
5 | 25–29 | Charcot–Marie–Tooth 2E | AD | NEFL | Point mutation c.23C>G (p.P8R) | ARMS-qPCR | 1 | 7 | 5/2 | 2 (4) | Fraternal twins livebirth |
6 | 30–34 | Huntington’s disease | AD | HTT | Trinucleotide expansion | Linkage analysis | 1 | 1 | 1/0 | 1 (1) | No implantation |
7 | 30–34 | ALS | AD | FUS | Point mutation c.1562G>A (p.R521H) | ARMS-qPCR + Linkage analysis | 1 | 1 | 1/0 | 1 (1) | No implantation |
8 | 35–39 | FAP | AD | TTR | Point mutation c.349G>T (p.A117S ) | ARMS-qPCR + Linkage analysis | 1 | 2 | 0/2 | 0 (0) | No transfer |
9 * | 25–29 | FAP | AD | TTR | Point mutation c.349G>T (p.A117S ) | ARMS-qPCR | 2 | 6 | 2/4 | 1 (2) | Identical twins livebirth |
10 | 30–34 | SMA | AR | SMN1, SMN2 | Deletion in exon 7 of SMN1 | ARMS-qPCR + Linkage analysis | 1 | 9 | 3/6 | 1 (1) | Singleton livebirth |
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Liao, C.-H.; Chang, M.-Y.; Ma, G.-C.; Chang, S.-P.; Lin, C.-F.; Lin, W.-H.; Chen, H.-F.; Chen, S.-U.; Lee, Y.-C.; Chao, C.-C.; et al. Preimplantation Genetic Diagnosis of Neurodegenerative Diseases: Review of Methodologies and Report of Our Experience as a Regional Reference Laboratory. Diagnostics 2019, 9, 44. https://doi.org/10.3390/diagnostics9020044
Liao C-H, Chang M-Y, Ma G-C, Chang S-P, Lin C-F, Lin W-H, Chen H-F, Chen S-U, Lee Y-C, Chao C-C, et al. Preimplantation Genetic Diagnosis of Neurodegenerative Diseases: Review of Methodologies and Report of Our Experience as a Regional Reference Laboratory. Diagnostics. 2019; 9(2):44. https://doi.org/10.3390/diagnostics9020044
Chicago/Turabian StyleLiao, Chun-Hua, Ming-Yuh Chang, Gwo-Chin Ma, Shun-** Chang, Chi-Fang Lin, Wen-Hsiang Lin, Hsin-Fu Chen, Shee-Uan Chen, Yi-Chung Lee, Chi-Chao Chao, and et al. 2019. "Preimplantation Genetic Diagnosis of Neurodegenerative Diseases: Review of Methodologies and Report of Our Experience as a Regional Reference Laboratory" Diagnostics 9, no. 2: 44. https://doi.org/10.3390/diagnostics9020044