Fig. 1: Phenotypic and dysmorphic features of patient 1 (A and B),...

Diagnosing Down Syndrome, Cystic Fibrosis, Tay-Sachs Disease And Other Genetic Disorders

Sometimes, a pediatrician will suspect that a child has a genetic disorder based on the child's symptoms or on the presence of dysmorphic features. For example, if a child has coarse facial features and developmental delays, a pediatrician may have reason to believe that the child has a form of mucopolysaccharidosis. Mucopolysaccharidosis is a family of diseases caused by an enzyme deficiency that leads to the accumulation of glycosaminoglycans (GAGs) within the lysosomes of cells. In one particular variant of this disease known as mucopolysaccharidosis I (MPS I), a deficiency of the enzyme alpha-L-iduronidase causes a build up of GAGs in tissues and organs, which in turn leads to a host of signs including skeletal deformities, coarse facial features, enlarged liver and spleen, and mental deficiencies. Because of the progressive nature of MPS I, a child might not exhibit noticeable symptoms until one to three years of age or even later, depending on severity.

There are a number of reasons that a pediatrician might refer a child to see a geneticist. Geneticists can confirm or rule out a physician's diagnosis based on the findings of a physical exam and various tests. In the case of a child with suspected MPS, if the enzymatic deficiency associated with the disorder is confirmed via testing, DNA analysis may also be performed to determine the exact genetic mutation causing the disorder. Because MPS I is inherited in an autosomal recessive fashion, identification of the mutation can allow the family to undergo carrier screening, as well as prenatal or preimplantation diagnosis in any future children.

Mom Had Three Kids With Down Syndrome. Then She Discovered She Has It, Too (Exclusive)

A mom of three discovered that she shares more than just DNA with her three kids — she shares their specific genetic mutation, too.

TikTok creator Ashley Zambelli, 23, went viral after she discovered that not only would she be having a third baby with trisomy 21 — also known as Down syndrome — but she herself had tested positive for the mutation. In a series of videos posted to her TikTok account, the mom of three shared her shocked reaction.

In one video, Zambelli writes, "My geneticist SHOCKED I'm having a baby with trisomy 21 for the 3rd time."

Across her videos, Zambelli shares that she has three children, two of whom have tested positive for trisomy 21. Zambelli experienced a pregnancy loss with a third baby who also tested positive for the mutation. When her geneticist noticed that she was having so many babies with this specific genetic mutation, Zambelli was prompted to get tested herself.

"Finding out I was pregnant with another baby that has trisomy 21 was definitely a shock to all of us," Zambelli tells PEOPLE exclusively. "It's not unheard of to conceive one to two since Down syndrome is, as far as we know, usually caused by a random failed separation of chromosomes during mitosis. But to have more than one or two? That's when this might not be a 'random' mutation."

Zambelli is mom to three young girls, Lillian, Evelyn, and Katherine.

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"Our oldest daughter Lillian has trisomy 21 and we can't wait to see [her and her sibling] grow up together, including our second daughter, Evelyn, who does not have Down syndrome. We are also very excited to see the person Evelyn grows to become since there's just something special about having siblings with Down syndrome."

Asked what inspired her to get herself genetically tested, Zambelli explains that it was actually her OB/GYN that came up with the idea. "She is the one who informed me that it's pretty rare to conceive a child with Down syndrome three times and wrote me a referral to a geneticist to see if I had a chromosomal abnormality."

Once Zambelli was tested, it came back positive for mosaic Down syndrome, or trisomy 21 mosaicism/mosaic trisomy 21.

According to the Stanford Children's Hospital, this form of Down syndrome is diagnosed when there's a mixture of two types of cells. Some have the usual 46 chromosomes and some have 47, which are the ones with the extra chromosome 21 that defines trisomy 21. Although this can cause babies born with mosaic Down syndrome to have similar features to babies with Down syndrome, it is also possible to have few features.

"When I got the call [with the diagnosis], I was happy! I've always had some miscellaneous complications throughout my life that never made sense to doctors, but now they do," Zambelli tells PEOPLE.

Although her kids are too young to understand their diagnoses, her friends and family were happy and supportive of Zambelli. "My friends and family were very surprised with my diagnosis...Everyone was very happy for me and supportive."

In her TikTok videos, Zambelli strives to create an educational platform where she can spread awareness about the genetic mutation. "TikTok has been such an amazing community to be in for spreading awareness of Down syndrome and the three forms of it — trisomy 21, mosaic, and translocation," she says. "All I can do is present the facts, keep spreading awareness, and hope to see a change."

As for the hardest part of her journey? "Encountering some people within the Down syndrome community. There have been a few who do not take me seriously and make me feel as if I need to prove my condition to them," the mom revealed.

"The stigma around Down syndrome unfortunately exists in our own community. I'm hoping that will change soon for the better."

HHMI Researchers Devise Prenatal Blood Test That Accurately Detects Down Syndrome And Two Other Serious Chromosomal Defects.

Howard Hughes Medical Institute researchers have developed a new prenatal blood test that accurately detected Down syndrome and two other serious chromosomal defects in a small study of 18 pregnant women. If confirmed in larger trials, they say, the test would offer a safer and faster alternative to invasive prenatal tests such as amniocentesis that pose a small risk of miscarriage.

Researchers have long known that a pregnant woman's blood contains small amounts of DNA from the fetus. Howard Hughes Medical Institute researcher Stephen R. Quake and colleagues at Stanford University devised an ingenious way to the scan fetal DNA present in the mother's blood to determine whether the fetus' cells contain extra chromosomes associated with several types of severe birth defects.

The test developed by Quake's team was more accurate than techniques used in previous efforts to diagnose aneuploidy by analyzing fetal DNA. Aneuploidy occurs when there are either too many or too few chromosomes in cells. Down syndrome, for example, is caused by a trisomy—three copies instead of two—of chromosome 21.

"We believe this is the first demonstration of a universal, noninvasive test for Down and other aneuploidies," said Quake, senior author of the research article, which was published online in the early edition of the Proceedings of the National Academy of Sciences (PNAS) on October 6, 2008. "We need a larger clinical study to understand a bit more about the best way to implement it, but I am highly optimistic it will be used as a diagnostic test in short order."

Amniocentesis and chorionic villus sampling (CVS), which are currently considered the "gold standard" in prenatal testing, involve sampling cells in amniotic fluid. Those cells are obtained by inserting a needle into the mother's uterus. The procedure carries up to a one percent risk of inducing a miscarriage. For that reason, routine use of these invasive diagnostic tests has largely been limited to women age 35 and older, where the age-related risk of fetal aneuploidy outweighs the risk of miscarriage. As a result, more infants with chromosomal defects are now being born to younger women. Researchers have been working for years to devise noninvasive screening tests that would be safe for that group of women.

In addition, it takes two or three weeks following the amniocentesis or CVS procedures to culture the cells and study the chromosomes. That amount of time can seem like an eternity for anxious parents waiting for the test results, Quake said.

With the new test, scientists only need to draw a small amount of blood from the woman. The blood is analyzed and the results are available within a couple of days, said Quake, who is a bioengineer at Stanford.

Quake's interest in developing new technology to diagnose aneuploidies was sparked when he read a research article published in the journal Science in 2005. That article discussed new methods of noninvasive prenatal testing that relied on measurements of DNA in fetal cells present in the mother's blood. The report said that the low prevalence of fetal cells—only about one in one million maternal cells—made it difficult to isolate enough of fetal cells to test for chromosomal abnormalities.

At the time, some researchers were trying to isolate fetal "cell-free DNA" from the mother's blood. Cell-free DNA is fragmented double-stranded DNA that is in the debris of dying fetal cells. Isolating this DNA was a good idea, Quake said, but recovering the vanishingly small amount of fetal cell-free DNA remained a challenge.

After reading the Science article, Quake thought to himself, `A lot of my work is about counting molecules; this is one problem I know how to do.' He had a brainstorm: Where other researchers were developing various ways of amplify the fetal DNA signal to distinguish it from maternal DNA, Quake proposed a bold shortcut—skipping that step entirely. After all, he observed, the point of screening was to spot extra chromosomes in the woman's blood sample. Whether the DNA being scanned was from the fetus or from the mother didn't matter. The objective, therefore, was simply to measure the amount of DNA in fragments mapped to the different chromosomes.

Conveniently, the cell-free DNA floating in the mother's blood circulation normally exists in short pieces, averaging 169 nucleotides in length. Quake proposed a "shotgun sequencing" strategy where he would use the very latest high-throughput gene sequencing technology and equally powerful computers to identify millions of unique sequence "tags" in the fetal DNA. Each of these tags was a 25 base-pair fragment of DNA. After the tags were identified, Quake's group could then map them to specific locations on the 23 pairs of chromosomes. By using this strategy, the researchers believed they could detect higher-than normal amounts of DNA belonging to the three chromosomes involved in the most common aneuploidies—chromosomes 21, 18, and 13.

In the experiments reported in PNAS, Quake and his colleagues, including first author H. Christina Fan, a graduate student in bioengineering at Stanford, used their new technique to analyze DNA in blood samples from 18 pregnant women who were undergoing invasive prenatal testing (and one man, for reference).

When the amounts of DNA corresponding to each chromosome were plotted on a graph, significant, above-normal peaks appeared when a chromosome was present in three copies instead of two. These signals enabled the scientists to correctly identify the 12 women who carried aneuploid fetuses and the six whose pregnancies were normal. Their results matched those of amniocentesis or CVS test that were done on the women.

Quake said the shotgun-sequencing system is not only safer than invasive techniques but can also make a determination at an earlier gestational age, around 12 weeks.

The earlier the couple knows the status of the pregnancy, Quake observed, the better they will be prepared for whatever decision they choose to make on the basis of the information.

Quake's group is now planning a follow-up study to evaluate the test in a larger group of patients. He estimates that the cost of the test during the next phase will be about $300, with DNA sequencing accounting for the majority of the overall cost.

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