Bloom syndrome is a rare, inherited genetic disorder characterized by short stature, increased skin sensitivity to sunlight, and a significantly higher risk of developing various cancers at an early age.
Individuals with Bloom syndrome tend to have a narrow face, a high-pitched voice, and a butterfly-shaped rash on the face, especially after exposure to the sun. Additionally, they may experience frequent infections, including ear infections and pneumonia, due to a weakened immune system.Â
The disorder affects both males and females, and males with Bloom syndrome are typically infertile. Bloom syndrome is more common in certain populations, particularly among people of Ashkenazi Jewish descent.
There is no cure for Bloom syndrome, but with proper medical care and monitoring, individuals can manage the symptoms and potentially prolong their life expectancy, though the risk of cancer remains a significant concern throughout their lives.
Bloom syndrome is caused by mutations in the BLM gene (BLM RecQ like helicase). The BLM gene is a gene that provides instructions for making a DNA helicase protein called Bloom syndrome protein (BLM). BLM plays a crucial role in maintaining the stability of DNA during cell division.
One of the key processes in cell division is DNA replication, where a copy of your full DNA is made so that each new cell receives a complete set of genetic material. DNA helicases are a group of enzymes that assist in this process by unwinding the double-stranded parent DNA, allowing replication to occur with limited recombination events. The BLM is part of this DNA helicase family. It plays a critical role in preventing excessive recombination between DNA strands. We will see what this means in the following section.
When a cell makes a copy of its DNA before dividing, sister chromatids are created. Sister chromatids are two identical copies of a chromosome. Sister chromatids are meant to be genetically identical. Sometimes, however, they exchange bits of DNA. This process is called sister chromatid exchange.
The role of the BLM gene is to keep this exchange within the normal level. Cells with a defective BLM gene make defective BLM protein that is unable to keep the sister chromatid exchange in check. Excessive sister chromatid exchange (or excessive DNA recombination) is a hallmark of Bloom syndrome.Â
When recombination happens too frequently or improperly, it can cause DNA to break, rearrange, or lose important genetic information. This genomic instability increases the risk of harmful mutations.Â
The most common BLM gene mutation, particularly in individuals of Ashkenazi Jewish descent, is a specific biallelic mutation known as the BLMASH mutation– a type of frameshift mutation. A frameshift mutation occurs when a DNA sequence is altered by insertions or deletions of nucleotides, disrupting the reading frame and leading to incorrect protein formation.
This particular mutation involves a 6-base pair deletion and a 7-base pair insertion (often referred to as c.2207_2212delinsTAGATTC) in exon 10 of the BLM gene. This alteration leads to a frameshift, causing the appearance of a premature stop codon in the mRNA. During protein synthesis, a stop codon is a signal for the enzymes to stop translating the mRNA into protein. As a result, the BLM protein is either incomplete or non-functional.
A 2020 study expanded our understanding of Bloom syndrome by identifying a new intronic variant that causes intron exonisation, where non-coding regions (introns) are incorrectly included in the protein-coding sequence (exons).
In one case, a patient with the typical symptoms of Bloom syndrome and a significant increase in sister chromatid exchanges was found to carry two BLM gene mutations: a novel nonsense variant in exon 18 (c.3379C>T, p.(Gln1127Ter)) and a deep intronic variant in intron 15 (c.3020-258A>G).
The intronic variant created a new splice site in RNA, leading to the retention of two intron segments, which introduced premature stop codons that halted BLM protein production, as confirmed by Western Blot analysis. This case underscores the significance of non-coding variants in Mendelian disorders and highlights the need for RNA-based testing to achieve a comprehensive molecular diagnosis.
Bloom syndrome is inherited in an autosomal recessive manner, meaning that a person must inherit two copies of the mutated BLM gene (one from each parent) to develop the disorder. If an individual inherits only one mutated BLM gene, they are considered a carrier of the disease but do not typically show symptoms.
When two carriers of the Bloom syndrome mutation have a child, there is a 25% chance that the child will inherit both mutated genes and have the syndrome, a 50% chance that the child will inherit one mutated gene and be a carrier, and a 25% chance that the child will inherit two normal genes and neither have the syndrome nor be a carrier.Â
Since Bloom syndrome is rare, it is most commonly observed in populations where genetic mutations are more frequent due to factors like geographic or cultural isolation. In the Ashkenazi Jewish population, for example, the frequency of carriers is higher, increasing the likelihood of children being born with the disorder.
Genetic counseling is often recommended for couples at risk of passing Bloom syndrome to their children, especially if there is a known family history of the disorder.
Bloom syndrome is typically diagnosed through a combination of clinical observations and genetic testing. Clinicians may first suspect the disorder based on physical symptoms, such as short stature, sun-sensitive facial rashes, and a history of frequent infections.
A confirmed diagnosis, however, usually requires genetic testing to identify mutations in the BLM gene. One method used to detect the disease is chromosomal analysis. This may reveal characteristic abnormalities, such as increased chromosome breakage and rearrangements. These abnormalities, a hallmark feature of Bloom syndrome, can be observed in a person’s isolated cells under a microscope. Â
Additionally, molecular genetic testing can be performed to directly sequence the BLM gene and identify the specific mutation causing the disorder. This type of testing is especially important in individuals with a family history of the syndrome or in populations known to have higher rates of BLM gene mutation.
Early diagnosis is crucial for managing the symptoms of Bloom syndrome, as affected individuals need close monitoring for early signs of cancer, infections, and other health complications.
Bloom syndrome can be detected prior to birth through prenatal genetic testing. If both parents are known carriers of a mutation in the BLM gene, they can opt for prenatal diagnostic tests, such as chorionic villus sampling (CVS) or amniocentesis, to determine whether their unborn child has inherited the disorder.
Chorionic villus sampling involves taking a small sample of cells from the placenta, usually between 10 and 13 weeks of pregnancy, while amniocentesis involves collecting amniotic fluid surrounding the baby, typically done between 15 and 20 weeks of pregnancy.
Both tests can be used to analyze the fetus’s DNA to see if it carries two copies of the mutated BLM gene, confirming a diagnosis of Bloom Syndrome.Â
Additionally, preimplantation genetic diagnosis (PGD) is an option for couples undergoing in vitro fertilization (IVF), allowing embryos to be tested for the syndrome before they are implanted into the uterus. This method helps reduce the risk of having a child with Bloom syndrome.Â
Bloom syndrome presents a variety of symptoms, many of which become noticeable in early childhood. The most common hallmark of the condition is short stature; individuals with Bloom syndrome tend to be significantly shorter than their peers throughout life.
Another prominent symptom is a sun-sensitive rash, often a butterfly-shaped pattern on the face that worsens with sun exposure. People with Bloom syndrome have a distinctive narrow face, prominent nose, and high-pitched voice. They also suffer from frequent infections, such as ear infections and pneumonia, due to a weakened immune system.Â
In addition to these outward signs, one of the most concerning features of Bloom syndrome is an increased risk of developing cancers at an early age. Individuals with the disorder are prone to various types of cancers, including leukemia, lymphoma, and cancers of the gastrointestinal tract and skin.
Other potential symptoms include learning disabilities, diabetes, and chronic lung disease. Males with Bloom syndrome are typically infertile, while females may have reduced fertility. Due to the variety of complications, especially cancer, regular medical monitoring is essential for managing the condition and detecting any health issues early.
Bloom syndrome is not curable, as it is a genetic disorder caused by mutations in the BLM gene that impair the body’s ability to repair DNA damage. However, the condition can be managed with proper medical care and regular monitoring to help address symptoms and reduce complications.
One of the primary concerns for individuals with Bloom syndrome is the increased risk of cancer, so early detection and treatment of cancers are crucial. This often involves regular cancer screenings, such as blood tests, imaging, and skin checks, to catch potential malignancies as early as possible.Â
Managing infections, which are more frequent in individuals with Bloom syndrome due to immune system deficiencies, is another important aspect of care. Antibiotics and other treatments can help prevent or address recurrent infections.Â
Since males with Bloom syndrome are typically infertile, fertility treatments or alternative family planning options may be explored if desired. Genetic counseling is also important for affected individuals and their families to understand the condition and make informed decisions about medical care and family planning.Â
Advances in genetic research may offer future treatments, but as of now, managing symptoms remains the primary approach.
Bloom syndrome is a rare genetic disorder caused by mutations in the BLM gene, leading to short stature, sun sensitivity, frequent infections, and a heightened risk of early-onset cancer. The BLM gene produces a helicase protein responsible for DNA repair and stability during cell division.
A cellular hallmark of Bloom syndrome is excessive sister chromatid exchange, where DNA segments are exchanged at higher rates, causing genomic instability and increased cancer risk.
The most common BLM mutation, particularly in Ashkenazi Jewish populations, is a frameshift mutation that disrupts protein synthesis. This syndrome is inherited in an autosomal recessive manner, requiring two mutated gene copies for the disorder to manifest.Â
Diagnosis is typically based on clinical symptoms and confirmed through genetic testing, while prenatal tests can detect the condition before birth. Although there is no cure for BS, regular monitoring for cancer and infections, along with genetic counseling, helps manage symptoms and complications.
Advances in genetic research, including RNA-based testing, offer hope for more precise diagnoses in a broader set of populations, as well asfuture targeted treatment options.
