AsianScientist (Oct. 1, 2014) – On September 19, 2014, the first in vitro fertilization (IVF) baby screened with multiple annealing and looping based amplification cycles (MALBAC) technology was born in the Peking University Third Hospital, China. This event is good news for patients with monogenic diseases, demonstrating the feasibility of this method of preimplantation screening to prevent disease transmission to the next generation.
Monogenic diseases are the diseases caused by one or a pair of mutated alleles, showing Mendelian inheritance patterns including autosomal dominant, recessive and X-linked inheritance. Most monogenic diseases can cause death, disability or congenital malformation and only a few can be treated effectively with existing medical treatments.
Pre-implantation genetic diagnosis (PGD) is a technique used to select healthy embryos for implantation during IVF. Currently, widely used PGD technologies include fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), comparative genomic hybridization and single-nucleotide polymorphism (SNP-array). These techniques either detect specific point mutations or chromosome abnormality, which is caused by chromosome segregation errors and is particularly common in older women.
Although it would be beneficial to simultaneously detect both monogenic point mutations and chromosome abnormalities, existing technologies are unable to do so. In contrast, MALBAC allows for the simultaneous detection of point mutations and chromosome abnormalities with high accuracy. Furthermore, the procedure uses low depth sequencing, allowing low cost and fast PGD.
MALBAC, a whole genome amplification method requiring only a single cell, was developed by Professor Sunney Xie’s team at Peking University’s Biodynamic Optical Imaging Center in 2012. Since MALBAC uses linear instead of exponential amplification, it is much more accurate and uniform than traditional PCR-based methods and can be used to analyze the genetic materials of small samples.
In collaboration with Professors Qiao Jie and Tang Fuchou from Peking University, Prof. Xie and his team demonstrated a proof of principle for the use of MALBAC in PGD, publishing their results in the journal Cell.
In this case, the man suffers from hereditary multiple exostoses, an autosomal dominant hereditary disorder, which is characterized by multiple bony spurs or lumps on the bones at an early age. He carries a frame-shift point mutation at the EXT2 gene, which has a 50 percent chance of being transmitting to his children. To avoid this risk, a normal embryo free from the disease allele was selected by Dr. Jie Qiao’s group at Peking University Third Hospital using the MALBAC technique developed in Professor Sunney Xie’s lab.
A total of 18 embryos at the blastocyst stage were obtained from the couple during an IVF cycle, and a few cells were biopsied from each of the day five or day six embryos. Genomic DNA was amplified evenly and accurately with the MALBAC method for the whole genome sequencing analyses.
Using their approach, the team identified three embryos with neither the inherited mutated allele nor chromosome copy number abnormalities and finally chose one healthy embryo to transfer into the woman. The embryo implanted successfully, grew normally and was shown to be free of aneuploidy and the mutated allele in amniotic fluid tests. Now, the baby has been born at a healthy weight of 4.03 kg. Umbilical cord blood genome detection further confirmed that the baby is free of the mutated allele.
The article can be found at: Hou et al. (2013) Genome Analyses of Single Human Oocytes.
Source: Peking University.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.