Oriental Network correspondents Chen Songchang and Zhang Li reported on June 16: On June 9, Xiao li's family ushered in a long-awaited baby, and his safe birth swept away the haze that hung over the family for a long time, and also touched the heart of the team of academician Huang Hefeng from the Obstetrics and Gynecology Hospital affiliated to Fudan University.
A maternity check-up is the beginning of a nightmare
The story begins seven years ago. Xiaoli and her husband are classmates, from campus acquaintances to enter the palace of marriage, all the way smoothly. Shortly after the marriage, Xiaoli became pregnant, and just as the whole family was immersed in the joy of preparing for the arrival of the new life, a maternity examination became the beginning of a nightmare: a large row of malformations was detected that the fetus had congenital heart disease and was accompanied by intrauterine growth restrictions. After careful consideration, Xiaoli and his wife decided to give up the child with difficulty. At that time, they had just moved to a new home, and naturally mistakenly thought that the decoration materials were not environmentally friendly enough, the ventilation time was not long enough, and the fetus had problems, and there was no genetic related examination.
After raising her body, Xiaoli readjusted her mood and began to prepare for pregnancy. The process of getting pregnant again went smoothly, and soon it was time for a large number of deformities. Unfortunately, this fetus also had a similar situation to the former fetus - congenital heart disease with intrauterine growth restrictions, and the same bad news once again hit the Xiaoli family. Since then, Xiaoli has begun a long road of seeking medical treatment everywhere, and has successively traveled to major hospitals in Zhejiang, Shanghai and other places, looking forward to finding a scientific and reasonable etiological explanation for the children in her belly.
Considering that they are not young, and have already carried out a major gestational induction in the last pregnancy, plus some of the heart problems of the fetus can be surgically repaired after birth, the induction of labor again is also a bit unbearable, and finally decided to give the fetus a chance. At 41+ weeks, the baby was born, but the phenotype was much more serious than expected: in addition to the heart problems detected by ultrasound, it also showed a special face, brain dysplasia, dystonia, dystonia, feeding difficulties, developmental delays, etc. At the same time, with the increase of age, the gap between children and peers is becoming more and more obvious, until the age of 2 years old, they still cannot sit alone, cannot speak, and have almost no response to external sounds. The miserable Xiaoli couple had to continue to take their children around for medical treatment, trying to figure out why they and her husband were obviously in good health, but they had similar problems in both consecutive births.
In this process, almost all genetically related tests are performed: gene chips, karyotype analysis of chromosomes, mitochondrial sequencing, total exon sequencing... Time and again, hope and disappointment ensued, the whole family was shrouded in darkness.
Can they still have a healthy child?
In the world's first case, the academician team discovered a new pathogenic gene
On the verge of giving up, Xiaoli and his wife came to Shanghai with the last glimmer of hope and turned to the team of academician Huang Hefeng for help. After carefully inquiring about the medical history and conducting a detailed phenotypic survey of the children, the team of Xu Chenming/Zhang Jinglan of the Genetic Center of the Obstetrics and Gynecology Hospital of Fudan University conducted a re-analysis of the sequencing data of the whole exome of the family lineage for Xiaoli and the child, and found that there were compound heterozygous variants on the R gene of the progenitors, which were inherited from their parents. Although the predicted variants are harmful and consistent in their genetic patterns, little is known about them as a new gene, and no specific disease has been definitively associated with it in current studies. At the same time, the child's mutated R gene interacts with the HNRNPK gene that causes Au-Kline syndrome, and the phenotype of the two-child child born by Xiaoli couple almost completely overlaps with Au-Kline syndrome, and Academician Huang believes that the data re-analysis found that the mutated R gene is most likely another new pathogenic gene of Au-Kline lineage disease.
Although it is felt that the R gene mutation is most likely to be the culprit that causes the poor reproductive history of Xiaoli and his wife, further functional experiments are still needed to verify, and animal experiments are an indispensable part. With the help of academician Li Jinsong's team at the Center for Molecular Cell Excellence and Innovation of the Chinese Academy of Sciences, the team used CRISPR/Cas9 to genetically edit haploid cells, construct "artificial sperm" carrying R gene mutations, and quickly construct mutant mouse models. The study found that the bialelecta variant of mice had significant differences in morphology and survival rate from wild-type/heterozygous mice, showing severe embryonic lethality or structural malformations, and biochemical experiments in vitro also confirmed the harmfulness of mutations to gene function.
With the help of the third generation of IVF, a healthy second child is born
The study of new genes is a relatively long process, but it also requires a little chance and luck. Visiting major genetic testing centers and public databases at home and abroad, there was no contact with another independent family. In the process of waiting, Xiaoli and his wife could not sit still.
As they age, the reserve function of the ovaries gradually declines, they are more and more eager to have a healthy child, but also afraid of missing out on the opportunity to have children forever because of age, hoping to use three generations of IVF technology (PGD) to eliminate embryos carrying R gene compound heterozygous variants. After repeated genetic counseling and full informed information from Academician Huang Hefeng and Director Xu Chenming, and after discussion and consent of the ethics committee, Xiaoli and his wife's PGD fertility request was approved. The first cycle yields 4 detectable embryos, but 3 of them have chromosomal abnormalities and the remaining 1 also carries a complex heterozygous variant of the R gene. The second cycle yields 5 detectable embryos, and fortunately, embryo No. 1 has neither chromosomal abnormalities nor two variants of the R gene. After the transplant, Xiaoli became pregnant smoothly, and the obstetric examination was all the way to the green light. In the second trimester, Xiaoli underwent a prenatal diagnosis at the Genetic Center of the Obstetrics and Gynecology Hospital affiliated to Fudan University, and once again confirmed that the fetus did not carry the same complex heterozygous variant of the R gene as the previous fetus, and other tests such as chromosomal karyotype and macroelexia were normal.
In the end, on June 9, Xiaoli gave birth to a 9.2-pound fat boy by full-term caesarean section, and the newborn was very healthy in all aspects. Xiao li, who was crying with joy, sent a thank-you letter to Academician Huang, thanking the team for its efforts, so that she finally got what she wanted and had a healthy and lovely baby.
In recent years, Huang Hefeng's team has helped many families like Xiaoli couples who are plagued by rare genetic mutations to produce healthy offspring. The team has created a number of research results/models of clinical application and transformation of technical systems, and a number of successful cases are the first in china and abroad, including: the first international case of successful fertility with chimeric PGD of gonad genes; For the first time, PGT was carried out in the family of hereditary thyroid cancer, colorectal cancer and other tumors, so that it could successfully produce healthy offspring; For the first time, PGT was used to achieve successful HLA matching, providing a guarantee for cord blood stem cell transplantation to treat the diseases of compatriots; The first genome-wide screening of healthy infants with PGT in Shanghai was born; The first single-cell high-throughput sequencing combined with karyotype localization in China was born in China for thyroid cancer "cancer-free" PGT babies; Help Ms. Yang, who lost her son in the second pregnancy 7 times due to carrying the "hemophagocytic syndrome gene", realize the "mother's dream" and block the family transmission of hemophagocytic syndrome; The first to use 1/50 of the size of oocytes for genetic testing, the "Madron deformity" mother's mother's dream; The world's first healthy newborn with Schaaf-Yang syndrome blocked by PGT technology. The research achievements of Academician Huang Hefeng's team have been promoted in 25 provinces, municipalities and autonomous regions across the country, which has effectively promoted the progress of assisted reproduction and PGT technology in other medical institutions in China, and has been approved as the Key Laboratory of Reproductive Genetics of the Ministry of Education, and has won the second prize of the National Science and Technology Progress Award twice with the first person to complete it.
Academician Huang Hefeng said that for couples who have given birth to children with new mutations or repeated same deformities, it is necessary to conduct genetic consultation before giving birth again, screen and diagnose the cause of the disease, and once sufficient evidence is obtained, the pathogenic genes and mutation sites can be clarified, and three generations of IVF (PGD) can be targeted to prevent the occurrence of birth defects.
Author: Liu Yilin
Source: Orient Net