On 19 February, 2015 the US Food and Drug Administration (FDA) authorised for marketing 23andMe’s Bloom syndrome carrier test, a direct-to-consumer genetic test to determine whether a healthy person has a variant in a gene that could lead to their offspring inheriting the serious disorder.
Along with this authorisation, the FDA is also classifying carrier screening tests as class II. In addition, the FDA intends to exempt these devices from FDA premarket review. The agency plans to issue a notice that announces the intent to exempt these tests and that provides a 30-day period for public comment. This action creates the least burdensome regulatory path for autosomal recessive carrier screening tests with similar uses to enter the market.
In general, carrier testing is a type of genetic testing performed on people who display no symptoms for a genetic disorder but may be at risk for passing it on to their children. A carrier for a genetic disorder has inherited one normal and one abnormal allele for a gene associated with the disorder. A child must inherit two abnormal alleles, one copy from each parent, in order for symptoms to appear.
No test is perfect. Given the probability of erroneous results and the rarity of these mutations, professional societies typically recommend that only prospective parents with a family history of a genetic disorder undergo carrier screening. For example, when a gene mutation is expected to be very rare, a positive result for the mutation may have a high probability of being wrong.
Like other home-use tests for medical purposes, the FDA requires the results to be conveyed in a way that consumers can understand and use. This is the same approach the FDA has taken with other over-the-counter consumer products such as pregnancy, cholesterol and HIV tests for home use.
While the FDA is not limiting who should or should not use these tests, it is requiring that the company explain to the consumer in the product labelling what the results might mean for prospective parents interested in seeing if they carry a genetic disorder.
If sold over the counter, the FDA is also requiring 23andMe to provide information to consumers about how to obtain access to a board-certified clinical molecular geneticist or equivalent to assist in pre- and post-test counselling.
23andMe performed two separate studies to demonstrate that their test is accurate in detecting Bloom syndrome carrier status. One study conducted at two laboratories tested a total of 123 samples, including samples from known carriers of the disease. An additional study evaluated 105 samples at two additional laboratories. Both studies showed equivalent results in detecting carrier status of Bloom syndrome when the same samples were tested.
The company also conducted a usability study with 295 people not familiar with the 23andMe saliva collection device to demonstrate consumers could understand the test instructions and collect an adequate saliva sample.
Finally, the company conducted a user study of 302 randomly recruited participants representing the US general population in age, gender, race and education level to show the test instructions and results were easy to follow and understand.
The test is intended only for postnatal carrier screening in adults of reproductive age, and the results should be used in conjunction with other available laboratory and clinical information for any medical purposes.
23andMe previously marketed a Personal Genome Service in the US but it ceased providing direct health information to US consumers after the FDA issued a 2013 Warning Letter. The letter directed the company to stop selling the product because of failure to obtain marketing clearance or approval to assure their tests were accurate, reliable and clinically meaningful. 23andMe is based in Mountain View, California.
Bloom syndrome is an inherited disorder characterised by short stature, sun-sensitive skin changes, an increased risk of cancer and other health problems.
People with Bloom syndrome have low birth weight and length. They remain much shorter and thinner than others in their family.
Affected individuals usually develop dilated blood vessels and reddening in the skin, particularly in response to sun exposure. These changes typically appear as a butterfly-shaped patch of reddened skin across the nose and cheeks. The skin changes may also affect the hands and arms.
People with Bloom syndrome have an increased risk of cancer. They can develop any of the cancers found in the general population, but the cancers arise unusually early in life, and affected individuals often develop more than one type of cancer.
Individuals with this disorder often have a high-pitched voice and distinctive facial features including a long, narrow face; a small lower jaw; a large nose; and prominent ears. Other features affecting some people with Bloom syndrome include learning disabilities, an increased risk of diabetes, chronic obstructive pulmonary disease, and recurrent infections of the upper respiratory tract, ears, and lungs during infancy. Men with Bloom syndrome usually do not produce sperm, and as a result are infertile. Women with the disorder generally have reduced fertility and experience menopause earlier than usual.
How common is Bloom syndrome?
Bloom syndrome is a very rare disorder in most populations, and its overall frequency is unknown. The disorder is more common in people of Central and Eastern European (Ashkenazi) Jewish background, among whom about 1 in 50,000 are affected. Approximately one-third of people with Bloom syndrome are of Ashkenazi Jewish descent.
What genes are related to Bloom syndrome?
Mutations in the BLM gene cause Bloom syndrome. The BLM gene provides instructions for making a member of a protein family called RecQ helicases. Helicases are enzymes that bind to DNA and temporarily unwind double helix of the DNA molecule. This unwinding is necessary for replicating DNA in preparation for cell division, and for repairing damaged DNA. Because RecQ helicases maintain the structure and integrity of DNA, they are known as the "caretakers of the genome."
When a cell prepares to divide to form two cells, the DNA that makes up the chromosomes is copied so that each new cell will get a complete set of chromosomes. The copied DNA from each chromosome is arranged into two identical structures, called sister chromatids, which are attached to one another during the early stages of cell division. Sister chromatids exchange small sections of DNA during this time.
The BLM protein interacts with several other proteins involved in the maintenance of genome integrity. With the help of its partner proteins, BLM suppresses sister chromatid exchanges and helps to maintain DNA stability during the copying process.
BLM gene mutations prevent the BLM protein from performing its function in maintaining genomic stability. As a result of the altered BLM protein activity, the frequency of sister chromatid exchange increases about 10-fold, which is a hallmark of Bloom syndrome. Increased sister chromatid exchange is an indicator of chromosome instability. It is associated with gaps and breaks in the genetic material that impairs normal cell activities and cause the health problems associated with this condition. Cancer results from genetic changes that allow cells to divide in an uncontrolled way. Altered BLM protein activity may also lead to an increase in cell death, resulting in slow growth in affected individuals.
How do people inherit Bloom syndrome?
This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.