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
Genotyping 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 | Genotyping 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-Ping 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