Xiaolu has been pregnant for 16 weeks and will have an amniocentesis soon. For the husband and wife, the result of this inspection will directly determine whether the child will stay in the belly.
Why is the result of sheep wearing so important? Because this is Xiao Lu's third pregnancy, she has given birth to a boy and a girl before that. Unfortunately, both brothers and sisters showed growth retardation and abnormal teeth arrangement. And the boy is 11 years old, and the girl is 8 years old. The
couple desperately need the professional doctors from Zhejiang University Women's Hospital to tell them whether has the child this time and whether it will continue to be pregnant.
Normal husband and wife
Why did they give birth to a sick child twice in a row? Z8z
Chief physician Dong Minyue and Dr. Qian Yeqing of the Reproductive Genetics Department of Zhejiang University Women’s Hospital found that Xiaolu and his wife had normal phenotypes and did not have any abnormal behaviors or mental problems. In the first generation, no other family history of mental retardation was found.
Moreover, the results of the birth checkup of Xiaolu's baby were not abnormal.
But in such a seemingly "normal" family, why would a child with mental retardation be given birth to two consecutive births?
"If this happens twice in a row, we first suspect it is genetically related." Director Dong Minyue said. But strangely, after checking the chromosomes of the two brothers and sisters born before Xiao Lu, no abnormalities were found. Doctors
performed a genome-level chromosome microarray examination, and found no disease-related mutations.
is in trouble now. saw Xiaolu's amniotic fluid puncture time coming soon. If the genetic cause of the abnormality of the first two babies cannot be found, then there is no clear direction for the amniocentesis, and there is no way to prevent Xiao Lu from giving birth to an intellectually disabled baby again.
Time is waiting for no one. Director Dong Minyue said, if the regular chromosome examination fails to find abnormalities, then use other techniques. According to
, the "culprits" that led to the birth of intellectually disabled children by Xiaolu and his wife are hidden deeply, and they certainly do not want to be discovered. However, for the health of the children, researchers from the Reproductive Genetics Department of Zhejiang University Women's Hospital have "packaged" several techniques and must dig out the cause of the disease.
They used the Nxclinical software to search for the keyword "mental disability, dental abnormality". After analyzing the chromosome microarray data of Xiao Lu's first two children, they conducted in-depth excavation and analysis and found that the two brothers and sisters have SATB2 gene exon 9 There is a "loss of heterozygosity".
They also used PCR technology to verify this result. After
, they checked literature and databases and found that the SATB2 (OMIM608148) gene is located in 2q33.1, and its mutation is related to the autosomal dominant SATB2-associated syndrome (SAS). The typical characteristics of
syndrome can also be seen from its name "S.A.T.B.2". S, severe speech anomalies (severe speech anomalies); A, abnormalities of the palate (cleft palate or high palate arch); T, teeth anomalies (teeth abnormal); B, behavioral issues with or without bone or brain MRI anomalies (abnormal behavior) With or without bone or abnormal MRI); and age of onset before 2 years of age (onset before 2 years of age).
These are all highly consistent with the symptoms of the two children from Xiaolu's family! that's it! The genetic cause has been found! With the help of technology, doctors discovered that the decisive factor that led to the birth of a child with the disease twice in a row was the loss of heterozygosity in the SATB2 gene. Z1z
stripped the cocoon, and asked for the root cause
scientists are also "detectives"
. It can also be seen from the figure below that such a small difference is indeed difficult to find by ordinary inspection.
is at the topFor the two children, you can see where the arrow points,
has several points below the horizontal line.
Xiaolu’s amniocentesis was performed at the 19th week of pregnancy. The results of the examination showed that the fetus’s chromosomal karyotype was normal, but the chromosome chip found that the fetus had the same deletion as Xiaolu’s previous two births. The B-ultrasound test also indicated that there was an interventricular septum. Defects-In layman's terms, Xiao Lu's fetus is likely to have intellectual disabilities and other problems like his brother and sister in the future. In the end, Xiao Lu and his wife decided to give up the child.
After learning from the pain, Director Dong Minyue and the others still have to help Xiao Lu achieve the goal of "birth a healthy child". However, the first two children and this birth are equivalent to the same deletion in the three consecutive births-when the parents do not have the deletion of exon 9 of the SATB2 gene, this obviously does not meet the characteristics of the new mutation! The great detective Sherlock Holmes once said, "All the possibilities are ruled out, and the rest is the truth." Scientists are sometimes detectives, and they discover the truth of life.
According to the actual situation of the couple and their sick fetus, the only theoretical possibility left is "gonadal mosaicism". "Through Gap-PCR and Sanger sequencing, we successfully found the breakpoints on both sides of exon 9 and found that the husband of pregnant women is highly likely to have SATB2 deletion mutations," said Qian Yeqing. Z1z
translates and summarizes the terminology. Doctors believe that it is very likely that there is a genetic problem in the husband's genes. They also obtained the semen and peripheral blood of Xiao Lu’s husband, extracted DNA for Gap-PCR testing, and found that there were mutations in the blood and semen.
This shows that Xiao Lu’s husband’s mutation is a systemic mosaic, not just a gonad mosaic. However, fluorescence quantitative PCR technology could not detect the abnormality of Xiao Lu's husband at this time, suggesting that the proportion of mosaicism is very low. Doctors in the Reproductive Genetics Department chose a more sensitive digital PCR technology to detect DNA in blood and semen. They found that the mosaic ratio of mutations in blood and semen was 13.16% and 16.68%, respectively.
This shows that there is a 13% to 16% probability of abnormalities such as intellectual disability in children born to Xiaolu and her husband. In this way, the probability of an abnormality in three consecutive births is about 2 in 1,000.
Although this is a small sounding number, it really happened to Xiao Lu and his wife.
How far is there to give birth to a healthy child
For Xiaolu and his wife, avoiding giving birth to a third child with intellectual disabilities is also a kind of help, but they need more than that. How
can help this family have a normal child is a difficult problem facing the Reproductive Genetics Department of Zhejiang University Women's Hospital.
Someone may ask: Why not use the third-generation IVF technology to determine a good embryo transfer and pregnancy?
This is because, as we said before, Xiao Lu’s husband’s mutation is a systemic chimerism, and the third-generation test tube needs to be haplotyped, and the heterozygous resolution of the haplotype cannot be less than 30%—— The chimerism of Xiaolu's husband is lower than this value, so the success rate of constructing haplotype is low.
For Xiaolu couple, natural pregnancy may be the better choice at present. However, now that the cause of the child's illness is known, as long as the targeted examination is carried out at the appropriate time, at least the next abnormal child can be avoided.
In fact, patients like Xiaolu’s husband and wife who have genetic abnormality mosaicism, find disease-causing genes combined with multiple genetic techniques, and take targeted treatment plans are not the only patients in the Department of Reproductive Genetics.
What causes the disease? Each family has its unique genetic code that needs to be "deciphered".
Although this is the powerlessness of mankind in the face of the "probability" of natural selection, this is a blessing in misfortune. With the advancement of technology, perhaps more unknown causes will be discovered in the future, and there will be more ways to help humans give birth to healthy children.
