On March 26th, the Huangpu Branch of the Obstetrics and Gynecology Hospital affiliated to Fudan University sent good news, and the world's first case of gonad gene chimeric PGT fertile baby was born here! Newborns are identical twins, the older brother is 2900g, the younger brother is 2720g, and the newborn score is 9 points (normal). This is also the world's first case of healthy offspring obtained by male gonadal gene mosaic with PGT fertility.
Four bad pregnancies, years of difficulty in finding a child
Before this success, Xiao Jia had four unforgettable memories: 2 fetal stops, 1 pregnancy in July, the baby was found to have multiple malformations to induce labor, and the fourth time, Xiao Jia, who was 38 years old, turned to assisted reproduction, hoping to "customize" a healthy baby through three generations of test tube technology, but this time also ended in failure: because the previous induced baby did not do a thorough genetic examination, only embryo chromosome screening and transplantation was carried out for advanced age indications, although the fetus's amniotic fluid examination suggested that the karyotype was normal. However, the obstetric examination of large rows of teratology found that the fetus was a multiple skeletal development abnormality. Fortunately, this time, the doctors did genetic testing on XiaoJia's fetus, and the test showed that the fetus had a hybrid SF3B4:c.29delA (p.Asn10 Ilffs*30) pathogenic mutation located on chromosome 1.
SF3B4 Pathogenic variants can lead to Nager syndrome, which manifests as acrometic hypoplasia and is characterized by craniofacial, severe micrognathic deformity, and zygomatic hypoplasia, and limb deformities.
▲Multiple bone development abnormalities caused by Nager syndrome Source: Courtesy of the interviewee (the same below)
After more than a year of healing, Xiao Jia and his wife once again embarked on the road of seeking a son. After reading the genetic test report, the doctor told the couple that the mutation in the fetus was a new mutation, and the possibility of having a baby like this fetus again was very small, and natural pregnancy could be considered, because neither husband and wife had detected the pathogenic mutation in the blood samples. However, Xiao Jia, who had experienced four heavy blows, was still worried, and after inquiring from many parties, she came to the reproductive genetics joint outpatient consultation of Academician Huang and Director Xu Chenming of the Obstetrics and Gynecology Hospital affiliated to Fudan University.
Break with tradition and find the culprit in the cells of the "right"
After carefully reviewing Xiao Jia's medical history, Academician Huang questioned the prognosis of natural pregnancy. Although the traditional view is that couples who give birth to children with new mutations have a lower risk of recurrence of re-pregnancy, only 1-2%, XiaoJia has two phenotypically similar malformed children's reproductive history, which cannot be judged by the traditional view alone, and the reproductive gland chimerism phenomenon of the couple needs to be further explored to determine the reproductive strategy of Xiaojia.
Chimerism refers to the phenomenon that the same individual cells developed from a single fertilized egg have different genetic compositions, chimerism can occur at the chromosomal level or at the gene level, and there are multiple patterns of distribution, including systemic distribution, limited to the distribution of a certain tissue, if chimerism occurs in the gonads (Figure 3B, Figure 4), although there is no genetic mutation in the blood sample of the parents, a second child can also be born, if the reproductive glands are in a complete chimeric state, the risk of fertility can be as high as 50%. That is, if the mutation is present in the father's sperm or the mother's egg, it cannot be detected at all after blood testing, and the "real culprit" can only be found in the germ cells.
▲Mosaic phenomenon
▲Male reproductive gland mosaic and offspring "new" mutations The child is born
But the process of "pursuing the culprit" is not easy, requiring laboratories to establish highly sensitive genetic testing technologies that can capture very low proportions of chimerism. In order to solve this problem, The team of academician Huang Hefeng has developed an ultra-high depth sequencing technology system for target sequence capture, which can amplify the detection sensitivity by at least 1,000 times compared with conventional sequencing technology, and does not let go of the clues of genetic abnormalities. After rigorous technical testing, the team conducted mutation detection of both partners' peripheral blood, oral mucosal cells and the man's sperm. Sure enough, the research team found pathogenic variants in the male sperm that were consistent with the precursors, accounting for about 2.6%.
After the test report, Academician Huang gave the couple two detailed genetic consultations, informing the precise proportion of chimerism and the possible risks, which can be considered for natural pregnancy + prenatal diagnosis escort, and three generations of test tube technology can also be considered to actively eliminate genetically abnormal embryos to help conceive. Couples who have experienced four adverse pregnancies this time strongly demanded three generations of IVF for fertility for the gene.
"Good brothers" achieved a long-cherished wish for many years
The couple who found the reason got the favor of fate in another three-generation IVF technology, the treatment process was smooth, academician Huang's team formulated a detailed treatment plan and embryo detection strategy for the couple, and Xiao Jia and his wife successfully got 3 integer polyploid blastocysts. After genetic testing, 2 did not carry the hybrid mutation, and the chief physician of the Reproductive Department Jinli chose one of the blastocysts for transplantation, and one was successful! Happily, the ultrasound found that it was actually twins, confirming that one blastocyst egg was split into identical twins.
Under the escort of Shen Jie's team from the Obstetrics department of Fudan University Obstetrics and Gynecology Hospital, Xiao Jia's pregnancy examination and prenatal diagnosis were also very smooth. Today, with the cooperation of the multidisciplinary team (reproduction, genetics, prenatal diagnosis, obstetrics) of the Affiliated Obstetrics and Gynecology Hospital of Fudan University, deputy chief physician of obstetrics Zhang Ying successfully delivered a caesarean section for the full-term Xiao Jia, and two healthy male treasures with the same egg were born for the second time.
Academician Huang pointed out that couples who have given birth to children with new mutations need to undergo genetic counseling before having children again to avoid or reduce the risk of recurrence. Especially for re-occurring "new-onset" mutant birth defects, the possibility of genital gland mosaicking needs to be considered.
Source: Xinmin Evening News