Skip to main content

Advertisement

Log in

Preimplantation Genetic Testing for Rare Inherited Disease of MMA-CblC: an Unaffected Live Birth

  • Reproductive Genetics: Case Study
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Methylmalonic acidemia combined with homocysteinemia and cobalamin C type (MMA-CblC, MIM # 277400) is a rare inherited disease with cobalamin metabolic disorder, which are caused by deficiency in the MMACHC gene. A couple with a proband child carried with compound heterozygous mutations of MMACHC (c.609G>A and c.567 dup T, NM_015506) sought for assisted reproductive technology to avoid the transmission of pathogenic genetic variants and unnecessary induction of labor. Thus, in vitro fertilization (IVF), preimplantation genetic testing (PGT), and prenatal genetic diagnosis were applied to fulfill this clinical demand. In this study, seven embryos were biopsied and carried out whole-genome amplification using multiple annealing and looping-based amplification cycle (MALBAC) method. Sanger sequencing together with copy number variation (CNV) analysis and single-nucleotide polymorphism (SNP) haplotyping was conducted to detect the mutated alleles and chromosomal abnormalities simultaneously. Three embryos (E07, E06, and E02) were confirmed without CNVs and inherited mutations at MMACHC gene. Embryo E07 with the best embryo ranking of 5BB was selected preferentially to transfer which led to a successful pregnancy and an unaffected live birth. Prenatal genetic diagnosing with amniotic fluid cells, Sanger sequencing with cord blood cells, and neonate MMA screening further verified our successful application of PGT in preventing mutated allele transmission for this rare inherited disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Thornhill AR, deDie-Smulders CE, Geraedts JP, et al. ESHRE PGD Consortium “Best practice guidelines for clinical preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS).” Hum Reprod. 2005;1:35–48.

  2. Harton G, Braude P, Lashwood A, Schmutzler A, Traeger-Synodinos J, Wilton L, et al. ESHRE PGD consortium best practice guidelines for organization of a PGD centre for PGD/preimplantation genetic screening. Hum Reprod. 2011;26:14–24.

    Article  CAS  Google Scholar 

  3. Carvalho F, Moutou C, Dimitriadou E, et al. ESHRE PGT consortium good practice recommendations for the detection of monogenic disorders. Hum Reprod Open. 2020;2020:hoaa018.

    Article  Google Scholar 

  4. Melnikova I. Rare diseases and orphan drugs. Nat Rev Drug Discov. 2012;11:267–8.

    Article  CAS  Google Scholar 

  5. Chang LJ, Huang CC, Yi-Yi T, et al. Blastocyst biopsy and vitrification are effective for preimplantation genetic diagnosis of monogenic diseases. Hum Reprod. 2013;28:1435–44.

    Article  Google Scholar 

  6. Morel CF, Lerner-Ellis JP, Rosenblatt DS. Combined methylmalonic aciduria and homocystinuria (cblc): phenotype–genotype correlations and ethnic-specific observations. Mol Genet Metab. 2006;88:315–21.

    Article  CAS  Google Scholar 

  7. Ya-Fen YU, Fang LI, Hong-Wei MA. Relationship of genotypes with clinical phenotypes and outcomes in children with cobalamin C type combined methylmalonic aciduria and homocystinuria. Zhongguo dang dai er ke za zhi= Chinese journal of contemporary pediatrics. 2015;17(8):769–74.

  8. Wang C, Li D, Cai F, Zhang X, Xu X, Liu X, et al. Mutation spectrum of MMACHC in Chinese pediatric patients with cobalamin c disease: a case series and literature review. Eur J Med Genet. 2019;62:103713.

    Article  Google Scholar 

  9. Gherasim C, Ruetz M, Li Z, Hudolin S, Banerjee R. Pathogenic mutations differentially affect the catalytic activities of the human b12-processing chaperone cblc and increase futile redox cycling. J Biol Chem. 2015;290:11393–402.

    Article  CAS  Google Scholar 

  10. Sloan JL, Achilly NP, Arnold ML, et al. The vitamin B12 processing enzyme, mmachc, is essential for zebrafish survival, growth and retinal morphology. Hum Mol Genet. 2020;29(13):2109–23.

    Article  CAS  Google Scholar 

  11. Chen M, Zhuang J, Yang JH, Wang D, Yang Q. Atypical hemolytic uremic syndrome induced by cblc subtype of methylmalonic academia: a case report and literature review. Medicine. 2017;96:e8284.

    Article  Google Scholar 

  12. Lerner-Ellis JP, Anastasio N, Liu J, Coelho D, Suormala T, Stucki M, et al. Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations. Hum Mutat. 2009;30:1072–81.

    Article  CAS  Google Scholar 

  13. Zhou W, Li H, Wang C, Wang X, Gu M. Newborn screening for methylmalonic acidemia in a Chinese population: molecular genetic confirmation and genotype phenotype correlations. Front Genet. 2019;9.

  14. Ji X, Zhang Z, Shi J, et al. Clinical application of NGS-based SNP haplotyping for the preimplantation genetic diagnosis of primary open angle glaucoma. Syst Biol Reprod Med. 2019;65(3):258–63.

    Article  CAS  Google Scholar 

  15. Gui B, Yang P, Yao Z, Li Y, Liu D, Liu N, et al. A new next-generation sequencing-based assay for concurrent preimplantation genetic diagnosis of Charcot-Marie-Tooth disease type 1a and aneuploidy screening. J Genet Genomics. 2016;43:155–9.

    Article  Google Scholar 

  16. Zong C, Lu S, Chapman AR, Xie XS. Genome-wide detection of single-nucleotide and copy-number variations of a single human cell. Science. 2012;338:1622–6.

    Article  CAS  Google Scholar 

  17. Schoolcraft WB, Treff NR, Stevens JM, Ferry K, Katz-Jaffe M, Scott RT Jr. Live birth outcome with trophectoderm biopsy, blastocyst vitrification, and single-nucleotide polymorphism microarray–based comprehensive chromosome screening in infertile patients. Fertil Steril. 2011;96:638–40.

    Article  Google Scholar 

  18. McArthur SJ, Leigh D, Marshall JT, et al. Pregnancies and live births after trophectoderm biopsy and preimplantation genetic testing of human blastocysts. Fertil Steril. 2005;84:1628–36.

    Article  Google Scholar 

  19. Huang J, Yan L, Lu S, et al. Validation of a next-generation sequencing–based protocol for 24-chromosome aneuploidy screening of blastocysts. Fertil Steril. 2016;105(6):1532–6.

    Article  CAS  Google Scholar 

  20. Yan B, Wang S, Jia H, Liu X, Wang X. An efficient weighted tag SNP-set analytical method in genome-wide association studies. BMC Genet. 2015;16:25.

    Article  Google Scholar 

  21. Eftychia D, Cindy M, Sophie D, et al. Principles guiding embryo selection following genome-wide haplotyping of preimplantation embryos. Hum Reprod. 2017;3.

  22. Hu T, Zhu H, Zhang Z, et al. Application of chromosomal microarray analysis for the diagnosis of children with intellectual disability/developmental delay and a normal karytype. Chin J Med Genet. 2017;34:169.

    Google Scholar 

  23. Hu B, Jin J, Guo AY, et al. Gsds 2.0: an upgraded gene feature visualization server. Bioinformatics. 2014;31:1296.

    Article  Google Scholar 

  24. Boycott KM, Vanstone MR, Bulman DE, MacKenzie AE. Rare-disease genetics in the era of next-generation sequencing: discovery to translation. Nat Rev Genet. 2013;14:681–91.

    Article  CAS  Google Scholar 

  25. Haghighi A, Krier JB, Toth-Petroczy A, et al. An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery. NPJ Genomic Med. 2018;3:1–10.

    Article  Google Scholar 

  26. Xi Y, Chen G, Lei C, et al. Expanded carrier screening in Chinese patients seeking the help of assisted reproductive technology. Mol Gen Genomic Med. 2020;8(9):e1340.

  27. Hou Y, Wu K, Shi X, et al. Comparison of variations detection between whole-genome amplification methods used in single-cell resequencing. Gigascience. 2015;4(1):s13742-015-0068-3.

  28. De Bourcy CF, De Vlaminck I, Kanbar JN, et al. A quantitative comparison of single-cell whole genome amplification methods. PLoS One. 2014;9:e105585.

    Article  Google Scholar 

  29. Huang L, Ma F, Chapman A, Lu S, Xie XS. Single-cell whole-genome amplification and sequencing: methodology and applications. Annu Rev Genomics Hum Genet. 2015;16:79–102.

    Article  CAS  Google Scholar 

  30. Semra K, Murat C, Beril Y, et al. The birth of a baby with mosaicism resulting from a known mosaic embryo transfer: a case report. Hum Reprod. 2020;3.

  31. Greco E, Minasi MG, Fiorentino F. Healthy babies after intrauterine transfer of mosaic aneuploid blastocysts. New Engl J Med. 2015;373:2089–90.

    Article  Google Scholar 

Download references

Acknowledgements

We thank the family for their cooperation and participation. We thank the embryology team at the Center of Reproductive Medicine for the help with sample preparation. We also thank Zhen liu and Jian Wu from Yikon Genomics for the technical help for data analysis.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Xinlian Chen or Shanling Liu.

Ethics declarations

Ethics Statement

The present study was approved by the Ethics Committee of West China Second Hospital of Sichuan University. All patients provided written informed consent.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Table S1

SNP haplotyping linkage analysis for the pedigree and embryo samples (DOCX 23 kb)

ESM 1

(PNG 866 kb)

High Resolution Image (TIF 2752 kb)

ESM 2

(PNG 379 kb)

High Resolution Image (TIF 2319 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Peng, C., Ren, J., Li, Y. et al. Preimplantation Genetic Testing for Rare Inherited Disease of MMA-CblC: an Unaffected Live Birth. Reprod. Sci. 28, 3571–3578 (2021). https://doi.org/10.1007/s43032-021-00621-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-021-00621-3

Keywords

Navigation