Optical Genome Mapping for the Molecular Diagnosis of Facioscapulohumeral Muscular Dystrophy: Advancement and Challenges
Abstract
:1. Introduction
2. Materials and Methods
2.1. Subjects
2.2. SB Analysis
2.3. Sample Preparation and OGM
3. Results
3.1. Data Quality and Processing
3.2. OGM vs. LGE
3.3. OGM vs. PFGE
3.4. Complex FSHD Cases
3.4.1. Somatic Mosaicism
3.4.2. Homozygous
3.4.3. Duplication
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Deenen, J.C.; Arnts, H.; van der Maarel, S.M.; Padberg, G.W.; Verschuuren, J.J.; Bakker, E.; Weinreich, S.S.; Verbeek, A.L.; van Engelen, B.G. Population-based incidence and prevalence of facioscapulohumeral dystrophy. Neurology 2014, 83, 1056–1059. [Google Scholar] [CrossRef] [PubMed]
- van Deutekom, J.C.; Wijmenga, C.; van Tienhoven, E.A.; Gruter, A.M.; Hewitt, J.E.; Padberg, G.W.; van Ommen, G.J.; Hofker, M.H.; Frants, R.R. FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit. Hum. Mol. Genet. 1993, 2, 2037–2042. [Google Scholar] [CrossRef] [PubMed]
- Wijmenga, C.; Hewitt, J.E.; Sandkuijl, L.A.; Clark, L.N.; Wright, T.J.; Dauwerse, H.G.; Gruter, A.M.; Hofker, M.H.; Moerer, P.; Williamson, R.; et al. Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy. Nat. Genet. 1992, 2, 26–30. [Google Scholar] [CrossRef] [PubMed]
- Lemmers, R.J.; van der Vliet, P.J.; Klooster, R.; Sacconi, S.; Camano, P.; Dauwerse, J.G.; Snider, L.; Straasheijm, K.R.; van Ommen, G.J.; Padberg, G.W.; et al. A unifying genetic model for facioscapulohumeral muscular dystrophy. Science 2010, 329, 1650–1653. [Google Scholar] [CrossRef]
- van Deutekom, J.C.; Bakker, E.; Lemmers, R.J.; van der Wielen, M.J.; Bik, E.; Hofker, M.H.; Padberg, G.W.; Frants, R.R. Evidence for subtelomeric exchange of 3.3 kb tandemly repeated units between chromosomes 4q35 and 10q26: Implications for genetic counselling and etiology of FSHD1. Hum. Mol. Genet. 1996, 5, 1997–2003. [Google Scholar] [CrossRef]
- Rieken, A.; Bossler, A.D.; Mathews, K.D.; Moore, S.A. CLIA Laboratory Testing for Facioscapulohumeral Dystrophy: A Retrospective Analysis. Neurology 2021, 96, e1054–e1062. [Google Scholar] [CrossRef]
- Lemmers, R.J.; Tawil, R.; Petek, L.M.; Balog, J.; Block, G.J.; Santen, G.W.; Amell, A.M.; van der Vliet, P.J.; Almomani, R.; Straasheijm, K.R.; et al. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat. Genet. 2012, 44, 1370–1374. [Google Scholar] [CrossRef]
- Lemmers, R.J.; van der Wielen, M.J.; Bakker, E.; Padberg, G.W.; Frants, R.R.; van der Maarel, S.M. Somatic mosaicism in FSHD often goes undetected. Ann. Neurol. 2004, 55, 845–850. [Google Scholar] [CrossRef]
- Lemmers, R.J.; Osborn, M.; Haaf, T.; Rogers, M.; Frants, R.R.; Padberg, G.W.; Cooper, D.N.; van der Maarel, S.M.; Upadhyaya, M. D4F104S1 deletion in facioscapulohumeral muscular dystrophy: Phenotype, size, and detection. Neurology 2003, 61, 178–183. [Google Scholar] [CrossRef]
- Lemmers, R.; van der Vliet, P.J.; Vreijling, J.P.; Henderson, D.; van der Stoep, N.; Voermans, N.; van Engelen, B.; Baas, F.; Sacconi, S.; Tawil, R.; et al. Cis D4Z4 repeat duplications associated with facioscapulohumeral muscular dystrophy type 2. Hum. Mol. Genet. 2018, 27, 3488–3497. [Google Scholar] [CrossRef]
- Nguyen, K.; Puppo, F.; Roche, S.; Gaillard, M.C.; Chaix, C.; Lagarde, A.; Pierret, M.; Vovan, C.; Olschwang, S.; Salort-Campana, E.; et al. Molecular combing reveals complex 4q35 rearrangements in Facioscapulohumeral dystrophy. Hum. Mutat. 2017, 38, 1432–1441. [Google Scholar] [CrossRef] [PubMed]
- Tawil, R.; Kissel, J.T.; Heatwole, C.; Pandya, S.; Gronseth, G.; Benatar, M.; Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Evidence-based guideline summary: Evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology 2015, 85, 357–364. [Google Scholar] [CrossRef] [PubMed]
- Lemmers, R.J.; O’Shea, S.; Padberg, G.W.; Lunt, P.W.; van der Maarel, S.M. Best practice guidelines on genetic diagnostics of Facioscapulohumeral muscular dystrophy: Workshop 9th June 2010, LUMC, Leiden, The Netherlands. Neuromuscul. Disord. NMD 2012, 22, 463–470. [Google Scholar] [CrossRef] [PubMed]
- Vasale, J.; Boyar, F.; Jocson, M.; Sulcova, V.; Chan, P.; Liaquat, K.; Hoffman, C.; Meservey, M.; Chang, I.; Tsao, D.; et al. Molecular combing compared to Southern blot for measuring D4Z4 contractions in FSHD. Neuromuscul. Disord. 2015, 25, 945–951. [Google Scholar] [CrossRef] [PubMed]
- Mitsuhashi, S.; Nakagawa, S.; Takahashi Ueda, M.; Imanishi, T.; Frith, M.C.; Mitsuhashi, H. Nanopore-based single molecule sequencing of the D4Z4 array responsible for facioscapulohumeral muscular dystrophy. Sci. Rep. 2017, 7, 14789. [Google Scholar] [CrossRef] [PubMed]
- Hiramuki, Y.; Kure, Y.; Saito, Y.; Ogawa, M.; Ishikawa, K.; Mori-Yoshimura, M.; Oya, Y.; Takahashi, Y.; Kim, D.S.; Arai, N.; et al. Simultaneous measurement of the size and methylation of chromosome 4qA-D4Z4 repeats in facioscapulohumeral muscular dystrophy by long-read sequencing. J. Transl. Med. 2022, 20, 517. [Google Scholar] [CrossRef]
- Lemmers, R.J.; Goeman, J.J.; van der Vliet, P.J.; van Nieuwenhuizen, M.P.; Balog, J.; Vos-Versteeg, M.; Camano, P.; Ramos Arroyo, M.A.; Jerico, I.; Rogers, M.T.; et al. Inter-individual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2. Hum. Mol. Genet. 2015, 24, 659–669. [Google Scholar] [CrossRef]
- Delourme, M.; Charlene, C.; Gerard, L.; Ganne, B.; Perrin, P.; Vovan, C.; Bertaux, K.; Nguyen, K.; Bernard, R.; Magdinier, F. Complex 4q35 and 10q26 Rearrangements: A Challenge for Molecular Diagnosis of Patients With Facioscapulohumeral Dystrophy. Neurology. Genet. 2023, 9, e200076. [Google Scholar] [CrossRef]
- Dai, Y.; Li, P.; Wang, Z.; Liang, F.; Yang, F.; Fang, L.; Huang, Y.; Huang, S.; Zhou, J.; Wang, D.; et al. Single-molecule optical mapping enables quantitative measurement of D4Z4 repeats in facioscapulohumeral muscular dystrophy (FSHD). J. Med. Genet. 2020, 57, 109–120. [Google Scholar] [CrossRef]
- Stence, A.A.; Thomason, J.G.; Pruessner, J.A.; Sompallae, R.R.; Snow, A.N.; Ma, D.; Moore, S.A.; Bossler, A.D. Validation of Optical Genome Mapping for the Molecular Diagnosis of Facioscapulohumeral Muscular Dystrophy. J. Mol. Diagn. JMD 2021, 23, 1506–1514. [Google Scholar] [CrossRef]
- Tonini, M.M.; Pavanello, R.C.; Gurgel-Giannetti, J.; Lemmers, R.J.; van der Maarel, S.M.; Frants, R.R.; Zatz, M. Homozygosity for autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) does not result in a more severe phenotype. J. Med. Genet. 2004, 41, e17. [Google Scholar] [CrossRef] [PubMed]
- Wohlgemuth, M.; Lemmers, R.J.; van der Kooi, E.L.; van der Wielen, M.J.; van Overveld, P.G.; Dauwerse, H.; Bakker, E.; Frants, R.R.; Padberg, G.W.; van der Maarel, S.M. Possible phenotypic dosage effect in patients compound heterozygous for FSHD-sized 4q35 alleles. Neurology 2003, 61, 909–913. [Google Scholar] [CrossRef] [PubMed]
- Lemmers, R.J.L.F.; Butterfield, R.; van der Vliet, P.J.; de Bleecker, J.L.; van der Pol, L.; Dunn, D.M.; Erasmus, C.E.; D’Hooghe, M.; Verhoeven, K.; Balog, J.; et al. Autosomal dominant in cis D4Z4 repeat array duplication alleles in facioscapulohumeral dystrophy. Brain 2023, awad312. [Google Scholar] [CrossRef] [PubMed]
Specimen ID # | Source | Methylation | SB-LGE | SB-PFGE | OGM | Shipping/Storing | Molecules ≥ 150 Kbp | N50 > 0.2 | Map Rate (%) | Effective Coverage | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
4q_1 | Outcome | 4q_1 | 4q_2 | Outcome | 4q_1 | 4q_2 | Outcome | ||||||||||||
FseI (delta1) * | U | U | A/B | U | A/B | U | A/B | U | A/B | ||||||||||
NHNN_FSH001 | UK | NA | >10 | No F1 No F2 | 23 | B | 24 | B | Negative | 23 | B | 24 | B | No F1, No F2 | d1, −80 °C | 332 | 0.277 | 94 | 166× |
NHNN_FSH002 | UK | NA | 7 | FSHD1 | NA | NA | NA | NA | - | 7 | A | 49 | A | FSHD1 | d1, −80 °C | 304 | 0.248 | 95 | 151× |
NHNN_FSH003 | UK | NA | 6 | FSHD1 | NA | NA | NA | NA | - | 6 | A | 39 | A | FSHD1 | d1, −80 °C | 382 | 0.340 | 93 | 147× |
NHNN_FSH004 | UK | NA | 8 | FSHD1 | NA | NA | NA | NA | - | 7 | A | 29 | A | FSHD1 | d1, −80 °C | 242 | 0.186 | 91 | 142× |
NHNN_FSH005 | UK | NA | >10 | FSHD2 | NA | NA | NA | NA | - | 18 | A | 24 | B | FSHD2 | d1, −80 °C | 293 | 0.228 | 65 | 106× |
NHNN_FSH006 | UK | NA | 1 | FSHD1 # | NA | NA | NA | NA | - | [1(64%);43(36%)] | A | 26 | B | FSHD1 mosaic | d1, −80 °C | 258 | 0.198 | 91 | 172× |
NHNN_FSH007 | UK | NA | 5 | FSHD1 | NA | NA | NA | NA | - | 5 | A | 27 | B | FSHD1 | d1, −80 °C | 220 | 0.158 | 88 | 145× |
NHNN_FSH008 | UK | −13 | 11 | No F1, No F2 | 10 | A | 10 | A | FSHD1 ^ | 10 | A | 10 | A | FSHD1 ^ | d1, −80 °C | 213 | 0.143 | 79 | 122× |
NHNN_FSH009 | UK | NA | 8 | FSHD1 | NA | NA | NA | NA | - | 7 | A | 18 | A | FSHD1 | d1, −80 °C | 203 | 0.120 | 75 | 83× |
NHNN_FSH010 | UK | NA | >10 | No F1, No F2 | 13 + 6 | A | 22 | A | FSHD dup | 13 + D | A | 22 | A | FSHD dup | d1, −80 °C | 203 | 0.142 | 83 | 131× |
IC_AIM_000950 | India | 0 | NA | - | 12 | B | 43 | A | No F1, No F2 | 12 | B | 42 | A | No F1, No F2 | 4 °C, d7, −80 °C | 251 | 0.131 | 80 | 134× |
IC_AIM_000918 | India | NA | NA | - | 2 | A | 23 | B | FSHD1 | 2 | A | 23 | B | FSHD1 | 4 °C, d7, −80 °C | 237 | 0.126 | 81 | 136× |
IC_AIM_000955 | India | NA | NA | - | 5 | A | 22 | A | FSHD1 | 4 | A | 22 | A | FSHD1 | 4 °C, d7, −80 °C | 228 | 0.118 | 74 | 105× |
IC_AIM_000957 | India | NA | NA | - | 5 | A | 39 | A | FSHD1 | 4 | A | 38 | A | FSHD1 | 4 °C, d7, −80 °C | 249 | 0.103 | 77 | 123× |
IC_AIM_000904 | India | NA | NA | - | 3 | A | 24 | B | FSHD1 | 3 | A | 24 | B | FSHD1 | 4 °C, d7, −80 °C | 220 | 0.094 | 67 | 107× |
IC_AIM_000963 | India | NA | NA | - | 4 | A | 25 | A | FSHD1 | 4 | A | 25 | A | FSHD1 | 4 °C, d7, −80 °C | 270 | 0.158 | 83 | 132× |
IC_AIM_000932 | India | −35 | NA | - | 9 | A | 12 | B | FSHD2 | 9 | A | 12 | B | FSHD2 | 4 °C, d7, −80 °C | 236 | 0.105 | 80 | 122× |
IC_AIM_001042 | India | −41 | NA | - | 19 | A | 19 | A | FSHD2 | 20 | A | 20 | A | FSHD2 | 4 °C, d7, −80 °C | 221 | 0.090 | 38 | 62× |
IC_AIM_001045 | India | NA | NA | - | 5 | A | 25 | B | FSHD1 | 4 | A | 25 | B | FSHD1 | 4 °C, d7, −80 °C | 213 | 0.100 | 64 | 112× |
IC_AIM_001053 | India | NA | NA | - | 4 | A | 21 | B | FSHD1 | 3 | A | 21 | B | FSHD1 | 4 °C, d7, −80 °C | 235 | 0.147 | 78 | 123× |
IC_AIM_001055 | India | NA | NA | - | 6 | A | 25 | A | FSHD1 | 7 | A | >11 | ND | FSHD1 | 4 °C, d7, −80 °C | 185 | 0.083 | 42 | 66× |
IC_AIM_000820 | India | NA | NA | - | 4 | A | 23 + 6 | AD | FSHD1 | 3 | A | 24 + D | A | FSHD1 | 4 °C, d5 | 212 | 0.161 | 78 | 51× |
IC_AIM_00152 | India | 16 | NA | - | 28 | A | 59 + 3 | AD | FSHD dup | 26 | A | 61 + D | A | FSHD dup | 4 °C, d5 | 289 | 0.234 | 88 | 102× |
IC_AIM_000701 | India | NA | NA | - | [2(40%);20(60%)] | A | 10 | B | FSHD1 mosaic | [2(36%);21(64%)] | A | 10 | B | FSHD1 mosaic | 4 °C, d5 | 260 | 0.177 | 80 | 128× |
IC_AIM_000531 | India | −8 | NA | - | 17 | B | 20 | A | No F1, No F2 | 17 | B | 21 | A | No F1, No F2 | 4 °C, d5 | 250 | 0.167 | 74 | 89× |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Efthymiou, S.; Lemmers, R.J.L.F.; Vishnu, V.Y.; Dominik, N.; Perrone, B.; Facchini, S.; Vegezzi, E.; Ravaglia, S.; Wilson, L.; van der Vliet, P.J.; et al. Optical Genome Mapping for the Molecular Diagnosis of Facioscapulohumeral Muscular Dystrophy: Advancement and Challenges. Biomolecules 2023, 13, 1567. https://doi.org/10.3390/biom13111567
Efthymiou S, Lemmers RJLF, Vishnu VY, Dominik N, Perrone B, Facchini S, Vegezzi E, Ravaglia S, Wilson L, van der Vliet PJ, et al. Optical Genome Mapping for the Molecular Diagnosis of Facioscapulohumeral Muscular Dystrophy: Advancement and Challenges. Biomolecules. 2023; 13(11):1567. https://doi.org/10.3390/biom13111567
Chicago/Turabian StyleEfthymiou, Stephanie, Richard J. L. F. Lemmers, Venugopalan Y. Vishnu, Natalia Dominik, Benedetta Perrone, Stefano Facchini, Elisa Vegezzi, Sabrina Ravaglia, Lindsay Wilson, Patrick J. van der Vliet, and et al. 2023. "Optical Genome Mapping for the Molecular Diagnosis of Facioscapulohumeral Muscular Dystrophy: Advancement and Challenges" Biomolecules 13, no. 11: 1567. https://doi.org/10.3390/biom13111567
APA StyleEfthymiou, S., Lemmers, R. J. L. F., Vishnu, V. Y., Dominik, N., Perrone, B., Facchini, S., Vegezzi, E., Ravaglia, S., Wilson, L., van der Vliet, P. J., Mishra, R., Reyaz, A., Ahmad, T., Bhatia, R., Polke, J. M., Srivastava, M. P., Cortese, A., Houlden, H., van der Maarel, S. M., ... Bugiardini, E. (2023). Optical Genome Mapping for the Molecular Diagnosis of Facioscapulohumeral Muscular Dystrophy: Advancement and Challenges. Biomolecules, 13(11), 1567. https://doi.org/10.3390/biom13111567