The day will come when a pregnant woman in her first trimester gives a sample of blood from a vein in her arm and within a few days receives exact and comprehensive data about the genetic condition of the fetus.
News that the baby will be normal should calm anxious parents; in the case of severe abnormalities, they will probably decide on an abortion. But in other – reversible – cases, surgeons could perform surgery or other treatments could be performed on the fetus in the womb so it can be born healthy.
Although infants could still be born with non-genetic defects, the possibility of the almost-perfect baby is coming.
Non-invasive prenatal testing (NIPT) is not yet so sophisticated, but it is already available for the asking (and paying) to screen fetuses for Down syndrome and a series of other fetal chromosomal defects.
DNA from the fetus circulates in mother’s blood. But unlike intact fetal cells in her blood, which can last for years after she gives birth, cell-free fetal DNA is the result of mostly placental cells that break down and are eliminated from the mother’s system within 30 minutes of giving birth. As a result, the fetal DNA that is present while the woman is pregnant tells the genetic story of the fetus in her uterus. When fragments of the fetus’s chromosomes are studied and measured, the actual defect can be named.
We can all thank Prof. Dennis Yuk-ming Lo, a 51-year-old researcher who created the whole field of NIPT. The chemical pathologist at the Chinese University of Hong Kong is director of the Li Ka Shing Institute of Health Sciences.
After learning from a colleague in the 1980s about polymerase chain reaction, a way of magnifying small amounts of DNA, Lo read a research paper describing the detection of tumor DNA in blood plasma.
The Hong Kong-born scientist speculated that it might be possible to detect fetal DNA in the blood of a pregnant woman. In 1989, he wrote a journal article suggesting that fetal DNA did exist in the mother’s blood, but only in small amounts. But eight years later, at John Radcliffe Hospital of the University of Oxford, Lo managed to detect fetal DNA in the plasma of its pregnant mother by using the male chromosome as a marker.
This pioneering work led to non-invasive diagnosis of various abnormalities in the young fetus. Three years ago, Lo developed a sequencing-based technology to determine the gender of the fetus earlier than an ultrasound scan can, and he adapted patented technology to use RNA, instead of DNA, to detect Down syndrome (Trisomy 21).
Since then, five different commercial firms, aware of the huge and profitable potential market, developed their own proprietary variations of NIPT, based on Lo’s work, and are offering them to pregnant women around the world. A physician has only to take the blood sample and airmail it to the company’s lab, which for a few thousand dollars provides the answers in up to two weeks. The companies are Natera, Ariosa, Sequenom, Verinata/Illumina (all American) and BGI (Chinese).
The Jerusalem Post learned that the head of the Health Ministry’s community genetics department, Prof. Joel Zlotogora, has requested that the public health basket committee include in the basket NIPT for pregnant woman at high risk of their fetus suffering from a serious genetic defect.
Inclusion in the basket means that the patient’s public health fund covers the cost of such treatment. About five percent of pregnant woman are considered to be at high risk.
Zlotogora said that instead of all pregnant women aged 35 and older being automatically entitled to free invasive testing, he preferred that high-risk women of any age be entitled to free NIPT. The invasive tests are amniocentesis (in which a small amount of amniotic fluid in the womb is removed by needle and examined) and chorionic villus sampling (in which placental tissue is tested). The two tests carry a very small risk of spontaneous miscarriage. Currently invasive testing in Israel is covered for all women age 35 and older, and for high-risk pregnancies – where high risk is determined by medical history, parental age, ultrasounds of the fetus and serum screens ( blood tests showing abnormal amounts of proteins, such as alpha-fetoprotein). NIPT is much more accurate than serum screens, and detects the main abnormalities associated with the woman’s age (especially Trisomy 21).
Although the lab tests cost up to NIS 6,000 apiece, Zlotogora is sure that the cost is sure to drop when the health funds order large numbers of them and the five companies compete to be suppliers.
ALTHOUGH THE ministry’s genetics expert and medical geneticists in the field decline to voice a preference for any specific screening test, the chief medical officer of one of them, Natera, volunteered to give an interview by Skype to the Post to discuss its NIPT product and the technology in general.
Prof. Susan Gross was appointed as first chief medical officer of the company in December and left her academic post at Yeshiva University’s Albert Einstein School of Medicine in New York. A specialist in clinical obstetrics and gynecology and women’s health, pediatrics and genetics at the medical school, she was a faculty member there since 1994.
“I have been carefully following the field of non-invasive prenatal diagnosis since its outset. There is no doubt that we are witnessing a watershed moment in perinatal medicine.” She decided to leave academia to join the company, which was founded by Dr. Matthew Rabinowitz in San Carlos in Silicon Valley.
Gross was born to a modern Orthodox family in Hamilton, near Toronto, and went to Bnei Akiva-affiliated schools. She received her medical degree at the University of Toronto, followed by a four-year residency in maternal/fetal medicine. She then completed a second residency in medical genetics at the University of Tennessee, Memphis.
Married to the president of a computer software company, she speaks some Hebrew and is the mother of three children (Tamar, Ilan and Daphna). The modern Orthodox family visit Israel on a regular basis, and while at Einstein, Gross had scientific collaborations with Israeli colleagues.
“The quality of Israeli geneticists and of obstetricians and geneticists is very high,” she noted. “Israel is well known for doing a lot of prenatal testing, as many women demand it,” said Gross. “This is not a uniquely Jewish phenomenon, but childbirth and respecting life are Jewish values.”
Although the company she works for is on the other side of the US, Gross lives in Riverdale in New York City, usually working from home but flying to the company when her presence is needed. “I want Natera to provide dignity to patients, not to focus just on the test but on the whole family. I learned from my clinical experience what families with genetic problems go through.” The company doesn’t have a branch in New York, but Gross works “from anywhere, meeting colleagues to find out what physicians and health-maintenance organizations require as services. I still love teaching and seeing patients, but because I wanted to do my job well, I decided to devote myself completely to Natera and leave my academic and clinical positions.”
HUMANS HAVE 23 pairs of chromosomes for a total of 46 – two copies of each set; the last pair determines sex (girls have two X chromosomes, and boys have one X and one Y). Medical and development problems occur when there are extra or missing chromosomes.
A trisomy occurs when there is an extra copy of any one chromosome, three copies instead of two. A monosomy occurs when there is a missing copy of any one chromosome, one copy instead of two. Triploidy occurs when there are three copies of all the chromosomes.
Trisomy 21, or Down syndrome, is caused by an extra copy of chromosome 21. The most common cause of of intellectual disability od varying severity, it may also cause certain birth defects of the heart or other organs and hearing or vision problems.
Trisomy 18, or Edwards syndrome, is caused by an extra copy of chromosome 18 and causes severe intellectual disability, as well as serious birth defects of the heart, brain and other organs. Babies with Edwards syndrome usually die before their first birthday.
Trisomy 13, or Patau syndrome, is caused by an extra copy of chromosome 13 and causes severe intellectual disability and other birth defects, with life expectancy usually no longer than one year. Monosomy X or Turner syndrome is caused by a missing X chromosome and affects only girls, who may have heart defects, hearing problems and minor learning disabilities.
As adults, they are often infertile.
Babies with triploidy suffer from severe birth defects, and the pregnancy can even endanger the mother because the condition can led to excessive bleeding after delivery and life-threatening seizures and can be associated with the development of cancer.
The infants usually die within a few months after they are born.
Other conditions include a vanishing twin, in which there is a multiple pregnancy but one of the fetuses dies in the womb.
Klinefelter syndrome involves an extra copy of the X chromosome and affects only boys, who may have learning disabilities, tend to be taller than average and are usually infertile as adults. Triple X syndrome is caused by an extra copy of the X chromosome and affects only girls, who may develop learning disabilities, be taller than average and could have emotional problems.
Gross maintains that Natera’s Panorama test “screens for more chromosome conditions than most of the other non-invasive tests. Natera is actively in the process of adding more conditions to the list.” It is also one of only two of the tests among the five companies to screen for microdeletions, in which a small part of a chromosome is missing.
These are rare, usually spontaneous and not the result of them being handed down by a parent or more common among older mothers (unlike Down syndrome). Some microdeletions cause intellectual disability and birth defects, while others have little impact on a child’s health and life, said Gross.
She stressed that NIPT tests like Panorama are a “revolutionary step forward” but do not replace amniocentesis and chorionic villus samples. If the screening results show evidence of a problem, an invasive test needs to be performed to get more information.
“The disorders we look for now are limited, but we are conducting research that will lead to more.”
DR. HAGIT Baris Feldman, director of the genetics institute at Haifa’s Rambam Medical Center, is well familiar with the various NIPT tests and works with three of them, including Natera; she knows Gross well, but she will not endorse one test over the other.
“Pregnant women here prefer to undergo a lot of noninvasive screening. There are numerous blood tests and ultrasound scans.
If something is suspicious, more tests are routinely done. I believe that about 25,000 amniocentesis procedures are carried out here every year. A DNA chip can be used to get information on more genetic problems from amniotic fluid that is removed.”
Her Rambam institute facilitates taking of blood samples for NIPT tests and performs comprehensive genetic counseling. The ministry has estimated that last year, 5,000 Israeli women pay privately for such screening.
Baris endorses the proposal that the blood tests be added to the basket of health services for high-risk women of any age. It would thus be available for all relevant patients and not only those who can afford them, she said.
Prof. Ephrat Levy-Lahad, head of the medical genetics institute at Jerusalem’s Shaare Zedek Medical Center, is also enthusiastic about the possibility of NIPT tests be included in the health basket, at least for high-risk cases. “The noninvasive blood are just the latest in a long list of tests offered to women who are either planning a pregnancy or are in its late stages, including carrier screening to detect couples at risk for Tay-Sachs and cystic fibrosis, various ultrasound tests and chromosomal arrays (the so- called DNA chip). Even gynecologists are not all aware of the various tests and their advantages and disadvantages,” she said.
“The need for a ‘Guide to the Perplexed’ has led us to create of the Bereshit clinic, a joint effort of Dr. Rachel Michaelson (ob/gyn and genetics) and Dr. Tamar Shalem (ob/gyn and prenatal ultrasound), which assists women in choosing the tests and followup appropriate for their particular concerns. The clinic serves as a “one stop shop” allowing women to formulate and coordinate a plan that suits them best.” Ultimately, Levy-Lahad concluded, “we will be able to know everything from the blood, and when parents get a normal result, it will be very reassuring. The problem will be to define what is normal.”