What Recessive Conditions Are Included in
Standard Carrier Screening Panels?

Cystic Fibrosis

Gaucher Disease

Cystic fibrosis is a genetic condition that causes mucus buildup in the body. This buildup can affect the lungs, leading to breathing difficulties and frequent infections. Additionally, cysts may form in the pancreas and block the ducts that release digestive enzymes, leading to difficulty obtaining nutrients from food. Cystic fibrosis can affect other organs as well, including the liver, sinuses, intestines, and sex organs. Management of cystic fibrosis typically involves clearing the airways, taking medication, and following a specific diet (3). Additionally there are targeted therapies based on someone's genetic status. 

Cystic fibrosis is caused by a variant in the CFTR gene. This gene controls the production of the cystic fibrosis transmembrane conductance regulator protein, an ion channel protein. Ion channels are tunnels that allow charged atoms or molecules to move in or out of the cell. The CFTR ion channel in the lungs moves chloride ions from inside the cell to outside the cell. Outside of the cell, these chloride ions attract water molecules, creating a water layer and thinning out the mucus. This water layer creates a sweeping motion that helps move mucus out of the lungs (4). 

Disease-causing variants in the CFTR gene can affect the CFTR protein in multiple ways. The protein may not function properly, may not be produced in adequate amounts, or may not be produced at all. All of these possibilities result in chloride ions becoming trapped inside the lung cells, reducing the amount of water drawn to the cell surface. The mucus in the airway then thickens, making it difficult to sweep out. This causes breathing issues in individuals with cystic fibrosis. Additionally, the mucus retains bacteria, allowing infections to grow (4). 

Gaucher disease is a lysosomal storage disease that causes fatty Gaucher cells to build up in the bone marrow, liver, and spleen. Gaucher cells are white blood cells that become full of the lipid substance glucocerebroside. This glucocerebroside backup can weaken the bones in a person’s body and enlarge the organs, causing them to malfunction. There are three types of Gaucher disease. Gaucher type 1 is the most common form found in the USA, and although there is no cure, it is treatable. This subtype affects the spleen, liver, bones, and blood, with symptoms including severe bruising, fatigue, and pain. Gaucher type 2 is rare, and affects children less than 6 months old. This subtype causes an enlarged spleen and severe brain damage. There is no treatment for Gaucher type 2, and patients usually pass from this condition between 2-3 years of age. Gaucher type 3 is the most common form worldwide, and appears before the age of 10. This subtype affects the bones and organs, as well as causing neurological effects. Patients with this subtype typically have a lifespan of 20-30 years (22, 23, 24). 

Gaucher disease is caused by a variant in the GBA1 gene, which is responsible for making the glucocerebrosidase (GCase) enzyme. GCase is a protein that has many functions, including the breakdown of glucocerebrosides. When the body does not produce enough GCase, fatty chemicals build up in the organs, bone marrow, and brain, affecting their functioning (22, 23, 24).

Gaucher disease can cause a range of symptoms and may impact the organs and blood in several ways. Fatty substances can accumulate in the lungs, affecting breathing. Lipids can build up in the bone marrow, destroying red blood cells and reducing oxygen delivery throughout the body, causing anemia and fatigue. Glucocerebrosides can build up in the spleen and liver, causing these organs to enlarge and become tender. This enlarged spleen traps platelets, causing easy bruising and the risk of heavy or prolonged bleeding. When there is reduced blood and oxygen delivery, the bones are also affected. Decreased blood flow can result in bone and joint pain. A lack of oxygen can cause bone tissue to fracture and die, known as osteonecrosis. When bones do not receive enough calcium, osteoporosis can occur, potentially leading to skeletal abnormalities (22, 23, 24).

Additionally, Gaucher types 2 and 3 can cause neurological symptoms such as feeding challenges and developmental delays, eye problems, seizures, and muscle spasms (22, 23, 24).

Sickle Cell Disease

Sickle cell disease is a genetic condition in which the body produces ‘C’ shaped red blood cells instead of the typical flat disc-shaped cells. These sickle-shaped cells can form clumps and block blood flow, preventing oxygen from reaching vital organs and tissues. As a result, individuals with sickle cell disease may experience episodes of severe pain. Sickle cells are also very fragile and burst apart more easily, leading to low levels of red blood cells, which can cause fatigue and weakness. Additional symptoms can include yellowing of the skin and whites of the eyes, swelling in the hands, feet, and joints, and an increased risk for serious complications such as a stroke (7 ,8). 

Sickle cell disease is caused by a variant in the HBB gene, a gene that is responsible for hemoglobin production. Hemoglobin is the component of the red blood cell that carries oxygen throughout the body. Changes in the HBB gene can cause the production of abnormal-shaped hemoglobin, called hemoglobin S. Red blood cells that contain this form of hemoglobin become rigid and sticky, causing them to clump together and block blood flow in small blood vessels (7). 

There are several different forms of sickle cell disease. The most common and severe form, known as sickle cell anemia, occurs when both copies of the HBB gene produce hemoglobin S, or sickle hemoglobin. Hemoglobin SC occurs when one copy of the HBB gene makes hemoglobin S, and the other copy of the gene makes a different abnormal hemoglobin, called hemoglobin C. This form of sickle cell disease usually causes mild to moderate symptoms. Another form of sickle cell disease is called sickle cell beta thalassemia. In this form, one copy of the HBB gene produces hemoglobin S, and the other copy has a beta thalassemia variant, which causes low hemoglobin levels. There are additional rare forms of sickle cell disease where one HBB gene produces hemoglobin S, and the other produces a different abnormal hemoglobin (7).

In order to have sickle cell disease, both copies of the HBB gene must contain a pathogenic variant. However, individuals with a variant on one copy of the gene have sickle cell trait. This can cause little to no symptoms or side effects, but the variant can be passed down to biological children (7).

Thalassemias

Thalassemias are blood disorders which affect the body’s ability to produce healthy red blood cells. Thalassemias specifically affect the production of hemoglobin, the oxygen-carrying protein within red blood cells. In individuals affected with thalassemia, there are fewer hemoglobin proteins produced. This shortens the lifespan of red blood cells and can lead to anemia symptoms (9). 

There are two types of thalassemias: alpha thalassemia and beta thalassemia. Hemoglobin is made of alpha protein chains and beta protein chains. The specific type of thalassemia that an individual has depends on the type of protein chain affected. The alpha protein chain of hemoglobin is made from four genes: two HBA1 genes and two HBA2 genes. When one or more of these genes contain a pathogenic variant, the person will be affected with alpha thalassemia. The symptoms of alpha thalassemia depend on how many genes are affected. If there is only one missing or mutated alpha gene, this is known as alpha thalassemia minima, and the person won’t exhibit symptoms. If there are two missing or mutated alpha genes, this is known as alpha thalassemia minor, and the person may or may not experience minor symptoms. If there are three missing or mutated alpha genes, this is known as hemoglobin H disease, and the person will have symptoms ranging from moderate to severe. If there are four missing or mutated alpha genes, this is known as hydrops fatalis with hemoglobin Barts, and this is often fatal at birth or may require lifelong blood transfusions. The beta protein chain of hemoglobin is made from two copies of the HBB gene. If there is one missing or mutated beta gene, this is known as beta thalassemia minor, and the person will have mild or no symptoms. If there are two missing or mutated beta genes, the person will have moderate to severe symptoms (9, 10, 11, 12, 13). 

Symptoms of thalassemia depend on the severity of the form. Milder forms of thalassemia can cause mild anemia, with symptoms including fatigue, weakness, dizziness, leg cramps, and pale skin. More moderate symptoms can affect the spleen and bones. Blood cells are made in the bone marrow, and in individuals with thalassemia, the marrow has to work harder to create enough blood cells. This may cause the bone marrow to grow bigger, expanding the bones and making them weaker. The spleen, which also produces red blood cells, may similarly enlarge from overexertion. Severe symptoms of thalassemia include lifelong anemia, poor appetite, jaundice, dark colored urine, and irregular facial bone structure. These severe forms may require blood transfusions or a bone marrow transplant (9, 10, 11, 12, 13).

If you are interested in reading a memoir about growing up in the 1960s with  Beta-Thalassemia Major, pick up a copy of “Iron Boy” by Arthur Bozikas online or at your local library.
*This is not a sponsored recommendation, and we receive no monetary incentive for this recommendation.

Spinal muscular atrophy (SMA)

Spinal muscular atrophy (SMA) is a group of genetic disorders that causes damage to lower motor neurons, leading to muscle weakness and decreased muscle movement. SMA usually affects muscles that are closer to the center of the body, and the muscle weakness gets progressively worse over time. There are five subtypes of SMA, which are classified by age of onset and severity. SMA type 0 affects a fetus prenatally, and infants with this subtype typically die at birth or within the first month of life. SMA type 1 is severe, and symptoms usually appear within the first six months, including breathing difficulties which can lead to death before the age of 2. SMA type 2 is intermediate, and symptoms typically appear between 6 and 18 months, with a life expectancy at around age 25. SMA type 3 is mild, and symptoms appear after 18 months. SMA type 4 is adult-onset, with symptoms beginning after the age of 21. SMA types 3 and 4 typically do not affect life expectancy (16, 17). 

The main symptom of SMA is muscle weakness, specifically in the muscles near the center of the body. Additional symptoms may include hypotonia, difficulty breathing and swallowing, lack of reflexes, and scoliosis (16, 17). 

SMA is caused by a variant in the SMN1 gene, or the survivor motor neuron 1 gene. The severity of the condition depends on how many copies of the SMN2 gene an individual inherits. The SMN1 gene produces the SMN protein, which is essential for motor neuron function. In SMA, the body does not produce enough of this protein. Without it, motor neurons waste away and die. As these neurons atrophy, the brain loses its ability to control voluntary muscle movements. The SMN2 gene also produces a small amount of the SMN protein, and a person can inherit up to 8 copies of this gene. Typically, individuals with more copies of this gene tend to have less severe SMA because their SMN2 genes are producing some of the required protein (16, 17). 

Congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) is a group of genetic disorders affecting the adrenal glands. The adrenal glands are located on top of each kidney and are responsible for producing hormones such as cortisol, which regulates stress, aldosterone, which maintains sodium levels, and androgen, which is a sex hormone. Individuals with CAH lack the necessary enzymes to make one or more of these hormones. There is both the classic form of CAH and the nonclassic form. The classic form is more severe and can cause complications, including shock and coma. There are two subtypes within the classic form of CAH: in the salt-wasting form, the adrenal glands do not produce enough aldosterone, resulting in sodium “being lost” from the body through urination. Additionally, there are low amounts of cortisol produced and high amounts of androgen. In simple virilizing CAH, the aldosterone deficiency is not as severe. However, there is heightened androgen production, which may result in symptoms related to sexual development. The nonclassic form of CAH is less severe, and symptoms may not present until adolescence or adulthood (14, 15). 

Symptoms of classic CAH may include ambiguous genitalia in female infants, an enlarged penis in male infants, premature puberty, and infertility. Additionally, in the salt-wasting form of CAH, symptoms can include severe dehydration, low blood pressure, an irregular heartbeat, vomiting, diarrhea, and shock. Symptoms of nonclassic CAH include acne, early puberty, excess facial or body hair in females, and male pattern baldness (14, 15). 

About 90-95% of CAH cases are caused by genetic variants in the CYP21A2 gene which create a deficiency of the 21-hydroxylase enzyme. This enzyme is critical for cortisol production, and when it does not function properly, the body does not produce enough cortisol. In response, the brain signals the adrenal glands to increase hormone production. However, because the cortisol pathway is blocked, hormone precursors accumulate and are redirected into producing other hormones, most commonly androgens. This cycle leads to an underproduction of cortisol and an overproduction of androgens (14, 15)

Canavan Disease

Canavan disease is a neurodegenerative disease that is part of a larger group of conditions called leukodystrophies. Leukodystrophies affect the myelin sheath, the white brain matter that covers neurons. The myelin sheath is a fatty substance that protects the nerves and promotes signal sending and receiving. There are two subtypes of Canavan disease. The infantile form is most common and more severe; patients often die in childhood or adolescence. Juvenile Canavan is less common and a milder form, and this subtype typically does not affect a patient’s life span (18, 19).

Canavan disease is caused by a variant in the ASPA gene. This gene is responsible for the production of the enzyme aspartoacylase (ASPA), which breaks down the compound N-acetyl-aspartate (NAA), found primarily in the brain. Individuals with Canavan disease do not produce enough ASPA, causing a buildup of NAA in brain tissue. This buildup damages the myelin, and over time, the brain deteriorates into spongy tissue, preventing it from functioning properly (18, 19).

Symptoms of infantile Canavan disease usually appear within 3-6 months of age and include abnormal muscle tone and lack of muscle control, developmental delays, difficulty chewing and swallowing, and a large head. These symptoms usually progress to hearing and vision loss, intellectual disability, and muscle spasms. Juvenile Canavan disease symptoms may include minor developmental delays and speech problems (18).

Tay-Sachs Disease

Tay-Sachs disease is a fatal condition affecting nerves in the brain and spinal cord. Symptoms usually appear around 6 months of age and include developmental delays and muscle weakness. These symptoms progressively worsen to vision and hearing loss, seizures, and paralysis, often leading to death between the ages of 2 and 5. There are two less common versions of Tay-Sachs; juvenile Tay-Sachs, where individuals develop symptoms at a later age and may live into their teenage years, and adult-onset Tay-Sachs which is typically less severe (5, 6).

Tay-Sachs is caused by a variant in the HEXA gene, which is responsible for making the enzyme beta-hexosaminidase A. This enzyme breaks down toxic substances called gangliosides in the body. The absence of this enzyme causes a fatty substance to collect in the brain and spinal cord nerve cells, damaging and destroying them (5, 6).