Spinal muscular atrophy (SMA) can be caused by mutations in a number of genes, usually the SMN1 gene. However, in a few cases SMA is caused by mutations in the DYNC1H1 gene. This gene encodes for a protein that is part of a motor protein complex called dynein. If dynein is ineffective in moving proteins and other materials around cells, the motor neurons in the spinal cord may not function properly. The SMA caused by the DYNC1H1 gene causes muscle weakness only in the lower limbs, particularly the thigh muscles, so is referred to as spinal muscular atrophy, lower extremity, dominant (SMA-LED). Sufferers find it difficult to climb stairs, get up from a chair, or walk long distances. The disease normally first occurs in childhood, but is not life-threatening. SMA caused by SMN1 defects is divided into different types; types 1-4 of SMA all involve muscle weakness. Type 1 SMA first occurs before 6 months. Affected babies are unable to hold their heads up or sit up. They typically have difficulty swallowing and breathing, and tend not to survive beyond the age of two. Type 2 SMA first occurs between 6 months and a year. Babies can sit up, but do not go on to stand or walk unaided in the usual manner. Type 3 SMA first occurs in older children. They can normally walk unaided, but may find climbing stairs or other similar tasks difficult. They may need to use a wheelchair by mid-life. Type 4 SMA first occurs in adulthood. Sufferers have some muscle weakness, tremors, and mild breathing problems. The incidence of spinal muscular atrophy (all types) is around 1 in 6,000 to 1 in 10,000 births. However, SMA from DYNC1H1 mutations only affects a small number of families. Unlike SMN1 defects, which are autosomal recessive, the mutations in DYNC1H1 are autosomal dominant. Typically, autosomal dominant inheritance require at least one affected parent.

Sources

NIH, Genetics Home Reference: DYNC1H1 gene.

See http://ghr.nlm.nih.gov/gene/DYNC1H1

NIH, Genetics Home Reference: Spinal Muscular Atrophy.

See http://ghr.nlm.nih.gov/condition/spinal-muscular-atrophy

Harms, M.B. et al. (2010), “Dominant spinal muscle atrophy with lower extremity predominance,” Neurology, 75, 539-546.

See http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2918478/

Long QT syndrome 11 (LQT11) is a heart condition caused by defects in the “A kinase anchor protein 9,” or AKAP9 gene, which encodes for protein AKAP9. It is involved in the anchoring of the protein kinase A enzyme complex in the cell and other cellular functions. In the heart, protein kinase A is involved in the activation of various ion channel proteins through phosphorylation, which are important for maintaining a regular heartbeat. Long QT refers to the abnormal signal on an electrocardiogram (ECG) seen with LQT patients. Such patients are at risk of episodes of increased heart rate, known as torsades de point, which may result in fainting or cardiac arrest. Death can sometimes occur, even in young people, so it is important that any fainting episodes are properly investigated. Treatment is by means of beta-blockers or implantable cardioverter-defibrillators (ICDs). Long QT syndrome types such as this, which only affect the heart, are also known as Romano-Ward syndrome. Overall, it’s estimated that about 1 in 2000 people, or 150,000 cases, suffer from LQT, some without knowing it. The condition does not seem to be more prevalent in any ethnic group. The affected gene is inherited in an autosomal dominant manner, which normally is inherited from one parent who also has the condition.

Sources

Alders, M. & Christiaans, I. (2003), “Long QT syndrome,” in Pagon, R.A. et al., editors, GeneReviews [Internet].

See http://www.ncbi.nlm.nih.gov/books/NBK1129/

Chen, L. et al. (2007), “Mutation of an A-kinase-anchoring protein causes long-QT syndrome,” Proc. Acad. Natl. Sci. U.S.A.,” 104, 20990 – 20995.

See http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409254/

NIH, Genetics Home Reference: AKAP9 gene.

See http://ghr.nlm.nih.gov/gene/AKAP9

NIH, Genetics Home Reference: Romano-Ward Syndrome.

See http://ghr.nlm.nih.gov/condition/romano-ward-syndrome

Usher syndrome is a condition that involves various degrees of deafness and gradual impairment of vision. Those with Usher syndrome type 1 are usually born deaf, and begin to lose vision while still children. A number of different genetic mutations can cause Usher syndrome type 1, including mutations in the CDH23 gene (Usher syndrome type 1D). CDH23 encodes for the protein cadherin 23, which is involved in cell aggregation, including aggregation in the retina and ear. The vision loss from Usher’s syndrome is due to the condition retinitis pigmentosa, which involves the gradual deterioration of retinal rod photoreceptor cells (leading to night blindness), followed by cone receptor cells (leading eventually to complete blindness). In addition to deafness, Usher syndrome type 1 affects the ability to balance. Children with the condition are typically slow to stand up and walk. The prevalence of Usher syndrome type 1 in the USA is over 4 in 100,000. The number due to CDH23 mutations is relatively low. In a survey of 34 families with members affected by Usher syndrome type 1, only 6 were affected by defects in the CDH23 gene. Usher syndrome type 1 is more common in certain ethnic groups, such as Ashkenazi Jews and the Acadians (Cajuns) of Louisiana. The condition is autosomal recessive, so typically an affected child will have two asymptomatic carrier parents.

Sources

NIH, Genetic Home Reference: CDH23 gene.

See http://ghr.nlm.nih.gov/gene/CDH23

NIH, Genetics Home Reference: Usher syndrome.

See http://ghr.nlm.nih.gov/condition/usher-syndrome

Roux, A.-F. et al. (2006), “Survey of the frequency of USH1 gene mutations in a cohort of Usher patients shows the importance of cadherin 23 and protocadherin 15 genes and establishes a detection rate of above 90%,” Journal of Medical Genetics, 43, 763-768.

See http://jmg.bmj.com/content/43/9/763.abstract

Familial thoracic aortic aneurysm and dissection, or familial TAAD, can be caused by defects in the MYH11 gene. The gene encodes for the myosin-11 protein, a contractile protein in smooth muscle. Cases of familial TAAD caused by defects in MYH11 are often associated with the condition Patent ductus arteriosus, or PDA, a congenital heart defect. The overall incidence of familial TAAD caused by MYH11 is low, accounting for only 1% of the total incidence of familial TAAD, which is itself only involved in around 20% of all cases of TAAD.

Sources

Pannu H1, Tran-Fadulu V, et al. MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II. Hum Mol Genet. 2007 Oct 15;16(20): 2453-62

See https://www.ncbi.nlm.nih.gov/pubmed/?term=17666408

Alpha Thalassemia, Aortic Dysfunctions, Beta Thalassemia, Bloom Disease, Canavan Disease, Cystic Fibrosis and CF related diseases, Familial Dysautonomia, Fanconi Anemia, Fragile-X, Galactosemia, Gaucher Disease, Glycogen Storage Disease Type IV, Long Q-T Syndrome, Maple Syrup Disease, Mucolipidosis Type IV, Niemann Pick Disease, Non-Syndromic Hearing Loss, OTC Deficiency, Phenylketonuria, Pompe Disease (Glycogen Storage Disease Type 2), Sickle Cell Disease (Anemia), Spinal Muscular Atrophy, Tay-Sachs and Usher Syndrome within others.

Familial thoracic aortic aneurysm and dissection, or familial TAAD, can be caused by defects in the MYLK gene. The gene encodes for the myosin light chain kinase protein found in smooth muscles. In patients with TAAD, the aorta increases in diameter, and dissection (blood flowing through the artery wall, following a tear) may occur at some point. In cases of TAAD caused by MYLK gene defects, it appears that dissection may occur without significant widening of the aorta. Rupture of the artery can follow, often leading to rapid death. Surgery is often required where a significant thoracic aortic aneurysm occurs. With proper management, life expectancy for those with familial TAAD can approach that of the general population. The incidence of familial TAAD caused by MYLK is low, accounting for only 1% of the total incidence of familial TAAD. Overall, familial TAAD is estimated to cause roughly 20% of thoracic aortic aneurysms and dissections. Approximately 10,000 deaths per year occur due to TAAD in the USA, so about 2,000 will be due to familial TAAD, giving around 20 deaths per year from MYKL defects, out of an overall USA total of around 2.6 million (0.001% of total deaths).

Sources

Centers for disease control and prevention, “Deaths: Final Data for 2013.”

See http://www.cdc.gov/nchs/fastats/deaths.htm

Milewicz, D.M. & Regalado, M., Thoracic Aortic Aneurysms and Aortic Dissections, (2003), Feb.13th, in Pagon, R.A. et al, editors. Genereviews [Internet].

See http://www.ncbi.nlm.nih.gov/books/NBK1120/

NIH, Genetics Home Reference: Familial TAAD.

See http://ghr.nlm.nih.gov/condition/familial-thoracic-aortic-aneurysm-and-dissection

Wang, L. et al. (2010), “Mutations in myosin light chain kinase cause familial aortic dissections,”Am.J.Hum.Genet.,87,701-707.

See http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2978973/

Glycogen storage disease II, also known as Pompe disease, is caused by mutations in the GAA gene. This gene encodes for the enzyme alpha-glucosidase, which breaks down glycogen into glucose. Without this enzyme, glycogen can build up to toxic levels, damaging muscles, including the heart muscles, as well as an inability to maintain normal fasting glucose levels. The classic form of the disease emerges in the first few months of life. Babies exhibit muscle weakness, breathing difficulties, heart problems, and fail to thrive. Mortality rates are high, few surviving the first year without treatment. A “non-classic” infantile form appears in the first year of life. Symptoms are similar, but the heart tends to be less severely affected. Even so, breathing difficulties mean that few survive for more than a few years without treatment. A late-onset form of the disease is also known, in which symptoms first appear during late childhood, adolescence, or adulthood. Here muscle weakness and respiratory problems arise, but usually the heart is unaffected. Most sufferers from this form die within 30 years of diagnosis without treatment. Enzyme replacement therapy, along with treatment for the various symptoms, can extend survival to some extent. The incidence of glycogen storage disease type II is around 1 in 40,000 in the USA, rising to 1 in 14,000 among African Americans. The carrier rate reaches about 1 in 60 in the latter population. The defective genes are inherited in an autosomal recessive manner, typically requiring both parents to be asymptomatic carriers for the faulty gene.

Sources

Leslie, N. & Tinkle, B.T. (2007), “Glycogen Storage Disease Type II (Pompe Disease),” in Pagon, R.A. et al., editors, GeneReviews [Internet].

See http://www.ncbi.nlm.nih.gov/books/NBK1261/

NIH, Genetics Home Reference: GAA gene.

See http://ghr.nlm.nih.gov/gene/GAA

NIH, Genetics Home Reference: Pompe Disease.

See http://ghr.nlm.nih.gov/condition/pompe-disease

Recombine Website: Glycogen Storage Disease, Type 2.

See https://recombine.com/diseases/glycogen-storage-disease-type-ii

After receiving genetic testing, it is recommended that you speak to a genetic counselor to best understand the impact of the test results. If you test positive for a hereditary cancer syndrome, it does not mean that you have cancer or that you will get cancer. Your provider can help you learn what preventative options you can take based on the risks associated to your cancer.

Arterial tortuosity syndrome (ATS) is caused by mutations in the SLC2A10 gene. The gene encodes for the protein GLUT10, which is believed to help regulate cell proliferation. Those with the syndrome have unusually long, often twisted, arteries which are prone to aneurysm (bulging), stenosis (constriction), and dissection (blood flowing through the torn artery wall). Arterial rupture, or constriction of the blood supply to vital organs, can lead to early mortality. Many sufferers die as children, although others may survive longer. Other symptoms of the syndrome include: elastic skin, very mobile or restricted joints, and various hernias. Sufferers tend to have elongated faces, widely spaced eyes (hypertelorism), and small chins. Arterial tortuosity syndrome is an extremely rare condition: only about 100 cases have been reported worldwide. The genetic abnormality is recessive, requiring one faulty gene from each parent. No evidence has shown more prevalence in any particular ethnic group.

Sources

Faiyz-Ul-Haque, M., et al. (2008), “Identification of a p.Ser81Arg encoding mutation in SLC2A10 gene of arterial tortuosity syndrome patients from 10 Qatari families,” Clinical Genetics, 74, 189-193.

See http://onlinelibrary.wiley.com/doi/10.1111/j.1399-0004.2008.01049.x/abstract-NIH

Genetics Home Reference: Arterial Tortuosity Syndrome.

See http://ghr.nlm.nih.gov/condition/arterial-tortuosity-syndrome

Nord Website, Arterial Tortuosity Syndrome.

See https://rarediseases.org/rarediseases/arterial-tortuosity-syndrome/

Understanding Negative Results

If your test returns a negative result, it means that there are no known mutations in your genes that are associated with higher risks for cancer. For this reason, you are at a significantly lower risk for developing a hereditary cancer. However, the possibility for cancer is not completely eliminated.

In some cases, cancer may be present in a family without any known genetic reason for hereditary cancer. If this is relevant to your family, you may still be at risk. In consult with your healthcare provider, you may want to consider increasing your rate of cancer screenings to closely monitor areas that your history may dictate has an elevated cancer risk.

There are two types of negative results:

True-negative - The person is not a carrier of a known cancer-predisposing gene that has been positively identified in another family.

Indeterminate - The person is not a carrier of a known cancer-predisposing gene, and the carrier status of other family members is either also negative or unknown.

Risk and Management:

You may have been prompted to take a cancer genetic test after discovering a family history of cancer. Alternatively, you may have had cancer already and want to understand your risk of the cancer returning, or the chance of developing other cancer types. Family history or personal cancer history may increase your cancer risk compared to the general population.

Your testing report provides you information regarding the cancers related to your potential gene mutation. Once you have the results, you can mitigate your cancer risk with several options:

• Increased screening to catch any potential cancers in their initial stages

• Certain medications may be prescribed depending on the relevant condition

• Lifestyle changes, including diet and exercise

• Surgery

Together with your healthcare provider, one or several of these options may be discussed and implemented to personalize your prevention or treatment.

Family:

Since your results may affect the health of other family members, it is important to discuss and share your results with them. They may decide to consult their healthcare providers to see how your results might affect them, including the option for genetic testing.

A genetic disease is a disease that is caused because of a mutation in an individual’s genetics. When this mutation is passed from parent to child, it is considered hereditary.

Bloom syndrome is caused by mutations in the BLM gene, which encodes for one of the RecQ helicase proteins. These proteins have an important role in preserving the integrity of DNA, as well as catalyzing key reactions that are crucial for DNA unwinding. Those with the disease have unusually short stature, and are very sensitive to sunlight, often having reddish marks on their faces. Men are sterile, while women have reduced fertility with an early onset of menopause. Most sufferers are of normal intellectual ability, although some suffer from learning difficulties. Cancer is much more likely in those with Bloom syndrome, often first appearing in their 20s or 30s. Early mortality from cancer is common, although sufferers often respond successfully to treatment. Bloom disease is an extremely rare condition, with about 300 cases known worldwide, about a quarter of which are among those Ashkenazi Jewish descent. The condition is autosomal recessive, which typically requires an affected child to have two asymptomatic carrier parents.

Sources

NIH, Genetics Home Reference: BLM gene.

See http://ghr.nlm.nih.gov/gene/BLM

NIH, Genetics Home Reference: Bloom Syndrome.

See http://ghr.nlm.nih.gov/condition/bloom-syndrome

Sanz, M. M. & German, J., (2006), “Bloom’s Syndrome,” in Pagon, R.A. et al., editors, GeneReviews [Internet].

See http://www.ncbi.nlm.nih.gov/books/NBK1398/

Recombine Website. Bloom Syndrome.

See https://recombine.com/diseases/bloomsyndrome

Loeys-Dietz Syndrome Type I is caused by mutations in the TGFBR1 gene. Other types of the syndrome are caused by faults in other genes. The TGFBR1 gene encodes the production of the TGF-β receptor 1 protein, which is believed to be involved in regulating cell proliferation. Those with the syndrome are liable to arterial aneurysms and tortuosity, along with hypertelorism (large distance between the eyes), cleft palates, and bifid (split) uvulae. Early mortality can occur due to arterial rupture. Loeys-Dietz Syndrome Type I is a rare condition, only found so far in a fairly small number of families. It is not yet possible to estimate its overall prevalence, or whether it is more common in particular ethnic groups. The Type 1 syndrome is believed to be the most common form of Loeys-Deitz syndrome. The defective gene is autosomal dominant, typically requiring at least one affected parent.

Sources

NIH, Genetics Home Reference: Loeys-Dietz Syndrome.

See http://ghr.nlm.nih.gov/condition/loeys-dietz-syndrome

NIH, Genetics Home Reference: TGFBR1.

See http://ghr.nlm.nih.gov/gene/TGFBR1

OMIM, Loeys-Dietz Sydrome 1.

See https://omim.org/entry/609192

Most people are born with 46 chromosomes. Chromosomes contain genes, which is where our DNA is. DNA is the “instructional manual” of the body. These 46 chromosomes are made of 23 pairs of chromosomes. We get one chromosome from each of our parents. This means that for each trait in our body (with rare exceptions) we have 2 chromosomes that determine what that trait will be.

In general, even if a person has different genes for a specific trait, only one of the genes will be visible. For example, if an individual has one gene for brown eyes and one for blue eyes, they will not have one brown eye and one blue eye. Instead they will have two brown eyes. This is because the gene for the color brown is “dominant.” Traits that are not dominant are called “recessive.” A recessive trait will only be apparent if the individual has two copies of that trait.

An exception to the rule above are traits known as “X-linked” traits. These traits are linked to the X chromosome. Females have two X chromosomes while males have one X chromosome and one Y chromosome. This means that males do not have one section of gene (the second leg of the “X”). For recessive traits that are on this gene, females, who have 2 “X” genes, will require two mutated genes; by contrast, males, who receive a “Y” gene from their Dad, will have the disease if they inherit a mutated gene from their mother. For this reason, “X-Linked recessive disorders” are much more common amongst men than they are in women. Examples of X-linked recessive disorders include Hemophilia A and Red-green color blindness.

Alpha Thalassemia is caused by defects in the HBA1 or HBA2 genes. These genes encode for the protein alpha-globin, a component of hemoglobin. There are two forms of the disease: Hb Bart syndrome and HbH disease. The former is more severe, affecting unborn babies. They suffer from general edema (swelling from fluid buildup), anemia, heart defects, and enlargement of the liver and spleen. Most are stillborn, or die within a few days of birth. Carrying an Hb Bart fetus may be harmful to the mother. HbH disease involves moderate anemia, jaundice, and enlargement of the liver and spleen. Abnormal skeletal changes are sometimes seen. Symptoms may begin in either childhood or adulthood. Generally, those with HbH can live a near-normal lifespan, although some may need blood transfusions if anemia becomes severe. The inheritance of the faulty genes is complex, but involves a number of categories of both carriers and those with symptoms. The disease is relatively common, particularly in South-East Asia. Other regions badly affected include India, the Middle East, Africa, and Mediterranean countries. Worldwide, about 1 in 48 people are carriers for the condition.

Sources

NIH, Genetics Home Reference: HBA1 gene.

See http://ghr.nlm.nih.gov/gene/HBA1

NIH, Genetics Home Reference: HBA2 gene.

See http://ghr.nlm.nih.gov/gene/HBA2

NIH, Genetics Home Reference: Alpha-thalassemia.

See http://ghr.nlm.nih.gov/condition/alpha-thalassemia

Origa, R. et al. (2005), “Alpha-Thalassemia,” in Pagon, R.A. et al., editors, GeneReviews [Internet].

See http://www.ncbi.nlm.nih.gov/books/NBK1435/

Recombine Website. Alpha-thalassemia.

See https://recombine.com/diseases/alphathalassemia

There are many reasons people get tested.

Patients with cancer or a history of cancer can use genetic testing to see if specialized and potentially more effective treatment options are available for them. These patients may also want to know if they are at increased risk for developing other "linked" cancers. Additionally, patients may want to know if their family members are at similar lifetime risk.

Patients without cancer, but with a family history of cancer, may want to get tested to see if they are at increased risk of developing cancer. This can help physicians create a personalized prevention plan.

The odds of being a carrier depend on the type of the disease and the individual’s ethnicity. In some studies, the incidence of testing positive as a carrier is as high as 25% or more when testing for a number of diseases at once. For cystic fibrosis, one of the more common diseases, the rates are:

Table 1. Cystic Fibrosis Detection and Carrier Rates Before and After Testing

Racial or Detection Carrier Risk Approximate Carrier Risk Ethnic Group Rate* (%) Before Testing After Test Negative Result† Ashkenazi Jewish 94 1/24 1/380

Non-Hispanic White 88 1/25 1/200

Hispanic White 72 1/58 1/200

African American 64 1/61 1/170

Asian American 49 1/94 1/180

*Detection rate data based on the use of a 23-mutation panel.

†Bayesian statistics used to calculate approximate carrier risk after a negative test result.

Modified from the American College of Medical Genetics. Technical Standards and Guidelines for CFTR Mutation Testing, 2006 Edition. Available at: http://www.acmg.net/Pages/ACMG_Activities/stds-2002/cf.htm. Retrieved December 16, 2010.

Genetic testing is generally done only once as genetics rarely change. A doctor might recommend testing for genes that were not previously tested for.

Beta Thalassemia is caused by mutations in the HBB gene, which encodes for the protein beta-globin, a subunit of hemoglobin. There are two forms of the disease, beta thalassemia major and beta thalassemia intermedia, the latter being less severe. With beta thalassemia major, symptoms develop before the age of two. Severe anemia is common, necessitating frequent blood transfusions. Other symptoms include jaundice, skeletal defects, and enlargement of the heart, liver, and spleen. Delayed adolescence may occur. Over time, excess iron from transfusions builds up in the body, and needs to be removed by chelation drugs. Premature death from cardiac mortality is common, but decreasing as treatments improve. Thalassemia intermedia is associated with mild anemia, some skeletal abnormalities, and in some cases growth inhibition. The worldwide incidence of beta-thalassemia is 1 in 100,000 new births. Regions with high levels of the disease include Mediterranean countries, the Middle-East, Central Asia, Africa, and the Far East. In the USA, those whose ancestors came from these regions have a higher risk of the disease than other ethnic groups. The mutated gene is inherited in an autosomal recessive manner, typically requiring both parents to be asymptomatic carriers of the faulty gene copy.

Sources

NIH, Genetics Home Reference: HBB gene.

See http://ghr.nlm.nih.gov/gene/HBB

NIH, Genetics Home Reference: Beta-thalassemia.

See http://ghr.nlm.nih.gov/condition/beta-thalassemia

Origa, R. (2000), “Beta-Thalassemia,” in Pagon, R.A. et al., editors, GeneReviews [Internet].

See http://www.ncbi.nlm.nih.gov/books/NBK1426/

Recombine Website. Beta-thalassemia.

See https://recombine.com/diseases/betathalassemia

Familial Thoracic Aortic Aneurysm and Dissection (Familial TAAD) and Loeys-Dietz Syndrome Type II can both be caused by different mutations in the TGFBR2 gene. The TGFBR2 gene encodes for the TGF-β receptor type 2, which is believed to be involved in the regulation of cell proliferation. Other types of Loeys-Dietz syndrome are caused by faults in other genes. Those with the syndrome are liable to arterial aneurysms and tortuosity, along with hypertelorism (large distance between the eyes), cleft palates, and bifid (split) uvulae. It is estimated that about 4% of the total cases of familial TAAD are due to mutations in the TGFBR2 gene. In patients with TAAD, the aorta increases in diameter, and dissection (blood flowing through the artery wall, following a tear) may occur at some point. Rupture of the artery may follow, often leading to rapid death. Surgery is often required where a significant thoracic aortic aneurysm occurs. With proper management, life expectancy for those with familial TAAD can approach that of the general population. The two conditions are separate: familial TAAD doesn’t give rise to the other symptoms seen with Loeys-Dietz Syndrome Type II. Loeys-Dietz Syndrome Type II is a very rare condition, only found so far in a fairly small number of families. It is not yet possible to estimate its overall prevalence, or whether it is more common in particular ethnic groups. The defective gene is autosomal dominant, typically requiring at least one affected parent. Familial TAAD comprises about 20% of the overall cases of TAAD. About 10,000 people in the USA die each year from TAAD, so around 2,000 of these will be due to familial TAAD, hence there are roughly 80 deaths per year from TAAD from TGFBR2 defects.

Sources

Centers for disease control and prevention, “Deaths: Final Data for 2013.”

See http://www.cdc.gov/nchs/fastats/deaths.htm

Milewicz, D.M. & Regalado, M., Thoracic Aortic Aneurysms and Aortic Dissections, (2003), Feb.13th, in Pagon, R.A. et al, editors. Genereviews [Internet].

See http://www.ncbi.nlm.nih.gov/books/NBK1120/

NIH, Genetics Home Reference: Familial TAAD.

See http://ghr.nlm.nih.gov/condition/familial-thoracic-aortic-aneurysm-and-dissection

NIH, Genetics Home Reference: Loeys-Dietz Syndrome.

See http://ghr.nlm.nih.gov/condition/loeys-dietz-syndrome

NIH, Genetics Home Reference: TGFBR2 gene.

See http://ghr.nlm.nih.gov/gene/TGFBR2

Testing positive means that you are a carrier for a specific disease, in other words, you have a single faulty copy of the gene. It does not mean that you have the disease, nor does it mean that your children will have the disease. If your partner is also a carrier of a positive mutation for the same gene (even if it is a different mutation) any offspring are at a 1 in 4 risk of inheriting the disease.

Mucolipidosis type IV is a disease caused by defects in the MCOLN1 gene, which encodes for the protein mucolipin 1. This protein is found in the membranes of lysosomes and endosomes, and is involved in the transport of various molecules. Mucolipin 1 is essential for the development and maintenance of the brain and retina. Infants with the disease typically develop poor motor skills, being slow to crawl, and rarely learning to walk or speak properly. Sufferers may have muscle weakness and difficulties swallowing. Visual impairment gradually advances, usually leading to complete blindness before the age of 10. Iron deficiency may occur as well. A small number of sufferers, about 5% of the total, develop a milder form of the disease, where they may be able to walk and talk. People with mucolipidosis type IV may live for many decades, although they tend to have a shortened lifespan. Overall, it’s estimated that about 1 in 625,000 people suffer from mucolipidosis type IV, although the figure rises to 1 in 37,000 among those of Ashkenazi Jewish descent, where about 1 in 100 may be carriers. The faulty gene is inherited in an autosomal recessive manner, which typically requires both parents to be asymptomatic carriers of the faulty gene copy.

Sources

NIH, Genetics Home Reference: MCOLN1 gene.

See http://ghr.nlm.nih.gov/gene/MCOLN1

NIH, Genetics Home Reference: Mucolipidosis Type IV.

See http://ghr.nlm.nih.gov/condition/mucolipidosis-type-iv

Recombine Website: Mucolipidosis Type IV.

See https://recombine.com/diseases/mucolipidosis-type-iv

Schiffmann, R. et al. (2005), “Mucolipidosis IV,” in Pagon, R.A. et al., editors, GeneReviews [Internet].

See http://www.ncbi.nlm.nih.gov/books/NBK1214/

Cancer testing is requested through your doctor. If your office is interested in testing and does not have kits, they can contact us at 201-825-0186 or email at shipping@geneidlab.com

Familial dysautonomia is caused by defects in the IKBKAP gene. This gene encodes for a protein called IKK complex-associated protein, which plays a role in protein transcription. Nerve cells are adversely affected when the protein fails to function. Children with the disease typically suffer from gastrointestinal problems (such as vomiting), feeding difficulties, somewhat stunted growth, muscle weakness, and a lack of sensitivity to pain or temperature. Sufferers are liable to suffer from lung infections far more than normal. Curvature of the spine and deterioration in vision often occur. Walking becomes increasingly difficult as adulthood is reached, and many patients reach the point where they are no longer able to walk unaided. Kidney damage is also common during adulthood. Early death is likely, often due to lung infections, although improvements to treatment mean that around half of all patients now survive to age 40. Familial Dysautonomia is normally found in those of Ashkenazi Jewish descent, where about 1 in 3,700 are affected; approximately 1 in 36 are carriers. The mutated gene is inherited in an autosomal recessive manner, which typically requires both parents to be asymptomatic carriers of the faulty gene copy. However, there have been cases of both male and female sufferers having children, although pregnancy is high risk for those with the condition. The offspring between affected patients and non-carriers will normally be asymptomatic carriers.

Sources

NIH, Genetics Home Reference: Familial Dysautonomia.

See http://ghr.nlm.nih.gov/condition/familial-dysautonomia

NIH, Genetics Home Reference: IKBKAP gene.

See http://ghr.nlm.nih.gov/gene/IKBKAP

Recombine Website: Familial Dysautonomia.

See https://recombine.com/diseases/familial-dysautonomia

Shohat, M. & Weisz Hubshman, M. (2003), “Familial Dysautonomia,” in Pagon, R.A. et al., editors, GeneReviews [Internet].

See http://www.ncbi.nlm.nih.gov/books/NBK1180/

The DNA sample is collected using mouthwash. It is simple and non-invasive.

After getting genetic testing, it is recommended that you speak to a genetic counselor to best understand the impact of the test results. If you test positive for a disease it is important to test your partner to determine whether they are also a carrier. If you are pregnant you may want to test the child as well, although some of the diseases have no cure, (and the range of severity can vary amongst people with the same disease), so it is a personal decision.

Your doctor or a local genetic counselor should be able to provide more information about cancer testing. You can find a genetic counselor through the National Society of Genetic Counselors (www.nsgc.com.)

Glycogen storage disease II, also known as Pompe disease, is caused by mutations in the GAA gene. This gene encodes for the enzyme alpha-glucosidase, which breaks down glycogen into glucose. Without this enzyme, glycogen can build up to toxic levels, damaging muscles, including the heart muscles, as well as an inability to maintain normal fasting glucose levels. The classic form of the disease emerges in the first few months of life. Babies exhibit muscle weakness, breathing difficulties, heart problems, and fail to thrive. Mortality rates are high, few surviving the first year without treatment. A “non-classic” infantile form appears in the first year of life. Symptoms are similar, but the heart tends to be less severely affected. Even so, breathing difficulties mean that few survive for more than a few years without treatment. A late-onset form of the disease is also known, in which symptoms first appear during late childhood, adolescence, or adulthood. Here muscle weakness and respiratory problems arise, but usually the heart is unaffected. Most sufferers from this form die within 30 years of diagnosis without treatment. Enzyme replacement therapy, along with treatment for the various symptoms, can extend survival to some extent. The incidence of glycogen storage disease type II is around 1 in 40,000 in the USA, rising to 1 in 14,000 among African Americans. The carrier rate reaches about 1 in 60 in the latter population. The defective genes are inherited in an autosomal recessive manner, typically requiring both parents to be asymptomatic carriers for the faulty gene.

Sources

Leslie, N. & Tinkle, B.T. (2007), “Glycogen Storage Disease Type II (Pompe Disease),” in Pagon, R.A. et al., editors, GeneReviews [Internet].

See http://www.ncbi.nlm.nih.gov/books/NBK1261/

NIH, Genetics Home Reference: GAA gene.

See http://ghr.nlm.nih.gov/gene/GAA

NIH, Genetics Home Reference: Pompe Disease.

See http://ghr.nlm.nih.gov/condition/pompe-disease

Recombine Website: Glycogen Storage Disease, Type 2.

See https://recombine.com/diseases/glycogen-storage-disease-type-ii

Partners who are both carriers have a number of options that they may consider when looking to conceive. The decision regarding what steps to take is a personal one and can vary significantly based on the specific disease and personal factors related to the couple. Some people may decide not to do anything. That said, some of the options include:

Conceive naturally

Prenatal Screening

In vitro fertilization; testing the egg for genetic diseases before it is implanted

Using a sperm or egg donor who is not a carrier

Adoption

Choose not to have children

Classical galactosemia is caused by mutations in the GALT gene. This gene encodes for the enzyme galactose-1-phosphate uridyltransferase, which is one of the enzymes that break down galactose. If the enzyme fails to function, increasing amounts of galactose-1-phosphate build up in the body, causing damage to tissues. The symptoms usually appear in the first few days of life. Babies suffer from vomiting, diarrhea, liver damage, jaundice, and fail to thrive. They are more susceptible to infection from bacteria such as E. coli than normal. Untreated babies usually die, or have severe brain damage. Feeding babies from birth on lactose-free formula milk is necessary. As they get older, a special diet absent of galactose and lactose is necessary. Even so, treated children are still at risk of poor growth, eye and speech problems, and mild intellectual disability. Women tend to suffer from premature ovarian insufficiency, so may not be able to have children. A “clinical variant” galactosemia, with slightly milder symptoms and without the increased risk of bacterial infection, has been described. This is also caused by defects in the GALT gene. Other types of galactosemia are caused by defects in other genes. The incidence of classical galactosemia has been estimated as 1 in 10,000 to 1 in 48,000 in the general population. The disease is particularly common among Irish travelers and their descendants, where up to 1 in 14 may be carriers, compared to about 1 in 125 in the general population. The “clinical variant” form is mainly found in African Americans. The disease is autosomal recessive, typically requiring both parents to be asymptomatic carriers of the faulty gene. If a sufferer has children with a partner who is not a carrier for the disease, the children will be asymptomatic carriers.

Sources

Berry, G.T. (2000), “Classic Galactosemia and Clinical Variant Galactosemia,” in Pagon, R.A. et al., editors, GeneReviews [Internet].

See http://www.ncbi.nlm.nih.gov/books/NBK1518/

NIH, Genetics Home Reference: Galactosemia.

See http://ghr.nlm.nih.gov/condition/galactosemia

NIH, Genetics Home Reference: GALT gene.

See http://ghr.nlm.nih.gov/gene/GALT

Recombine Website: Classical Galactosemia.

See https://recombine.com/diseases/classical-galactosemia

In some cases, a parent may have a mutation for a disease, but the gene has incomplete penetrance and the disease does not occur until later in life, if at all. For this reason, it is important to test for certain diseases that are passed on in an autosomal dominant fashion, even though none of the parents show symptoms of the disease.

There are several reasons why many types of individuals should consider carrier testing:

The American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics (ACMG) recommend offering screening for some genetic diseases to all patients who are considering having a child

Many ethnicities, including Caucasian, African American, Hispanic, Ashkenazi Jewish and others who are at increased risk for certain genetic diseases

Individuals with family members who have had an inherited disease, or have a known carrier mutation in the family, are at high risk of having a mutation

Egg or sperm donors may require carrier testing

Ornithine transcarbamylase deficiency is caused by mutations in the OTC gene. This gene encodes for the enzyme ornithine transcarbamylase, which carries out a key step in the urea cycle. The liver alters toxic ammonia and converts it to urea, a much safer is converted into urea, a much more neutral compound. If the enzyme is partially or wholly inactivated, damaging levels of ammonia will tend to build up in the body. The condition is much more common in males than females. Symptoms often occur within the first few days of life. They include poor feeding, muscle weakness, lethargy, seizures, and hyperventilation. Severe hypothermia and brain damage result if prompt treatment is not started. Dialysis and nitrogen scavenger compounds, such as sodium benzoate, can be used to remove ammonia from the body. Even when ammonia levels appear to be under control, a crisis can appear in which they become elevated again. Low protein diets are needed throughout life. Infants may even require a liver transplant. A late-onset form of the disease can commence later in life, sometimes triggered by injuries, operations, or starting a high protein diet. Typical symptoms include mental problems, headaches, and vomiting. The incidence of the disease is roughly 1 in 70,000 births, occurring in roughly 4,300 patients in the USA. There does not seem to be huge differences in its occurrence among different ethnic groups. The faulty gene resides on the X chromosome, also known as an X-linked disease. Unlike females, any male with the faulty gene will have the disease since males only have a single X chromosome. The severe version of the disease is very rare in females, since they would need two faulty genes, which is highly unlikely. Females with one faulty gene normally act as carriers with no symptoms, however 15% of them will show some symptoms during their lifetime. As the disease is linked to the X chromosome, affected fathers cannot pass it on to their sons. Their daughters of affected fathers will normally receive the faulty gene.. Mothers with the faulty gene, whether they are asymptomatic or not, have a 50% chance of passing it on to each child.

Sources

Lichter-Konecki, U. et al. (2013), “Ornithine Transcarbamylase Deficiency,” in Pagon, R.A. et al., editors, GeneReviews [Internet].

See http://www.ncbi.nlm.nih.gov/books/NBK154378/

NIH, Genetics Home Reference: Ornithine Transcarbamylase Deficiency.

See http://ghr.nlm.nih.gov/condition/ornithine-transcarbamylase-deficiency

NIH, Genetics Home Reference: OTC gene.

See http://ghr.nlm.nih.gov/gene/OTC

Recombine Website: Ornithine Transcarbamylase Deficiency.

See https://recombine.com/diseases/ornithine-transcarbamylase-deficiency

Even without any history of genetic disease in your family there are reasons to consider genetic testing. Although most hereditary diseases are fairly uncommon, approximately 80% of all recessive diseases occur in families with no known family history. This is because the diseases only occur when a person has two defective (mutated) genes, one from each of their parents. It is often the case that no one in the family had the disease for generations because individuals only had a single copy of the defective gene. People with one copy of the mutation are referred to as “carriers” for the specific disease. Although the parents themselves are healthy, they do “carry” a faulty gene and can pass it down to their children.

Carrier testing is generally only done once as genetics rarely change. A doctor might recommend testing for diseases that were not previously tested for.

Your doctor or a local genetic counselor should be able to provide more information about carrier testing. You can find a genetic counselor through the National Society of Genetic Counselors (www.nsgc.com.)

Carrier testing is requested through your doctor. If your office is interested in testing and does not have kits, they can contact us at 201-825-0186 or email at shipping@geneidlab.com

The DNA sample is collected using mouthwash and a cheek swab. It is simple and non-invasive.

Getting tested at the same time is not necessary, but will save time if one of the partners is a carrier for a disease. Often the female partner will get tested first, and the male partner will get screened if she tests positive for a disease, although either partner can be tested independently.

NewbornGene ID offers 2 testing options:

• NewBornGene Panel - 62 genes covering 24 different types of conditions (testing covers many different types of conditions, for example there are multiple types of Usher Syndrome tested for)

• Cystic Fibrosis Screen

The explanation of benefits is a statement of charges created by your insurance company. The information included usually has the details of the services performed, the provider's charges, and how the charges are being processed by your insurance company. This information is an explanation for the patient and should not be confused with a bill.

Most in-network patients have little to no out of pocket costs associated with genetic testing. Talk to your physician to see if your insurance covers genetic testing.

Yes! GeneID offers a private pay option for individuals that are out of network or do not currently have health insurance. Call us at 1-866-436-3263 to learn more about our private pay and payment plan options.

Fragile-X Syndrome is a genetic disease caused by a mutation on the X chromosome. According to the National Institute of Health (NIH) and the National Center for Biotechnology Information (NCBI), it is the most common form of inherited intellectual and developmental disease. Following the recommendation of The American Congress of Obstetricians and Gynecologists (ACOG), Fragile-X Syndrome testing should be included in any carrier test if it is specifically requested for by the female patient.

A genetic mutation, also known as a genetic variant, is a change in the DNA. While most changes in our DNA are harmless, occasionally a DNA change can have serious consequences, including an increased risk for cancer or for a serious genetic disease. Several types of mutations are possible:

1. "Substitutions"

   1. "Missense Mutations" – a change in a single letter of DNA that leads to a change in the protein produced

   2. "Nonsense Mutations" – a single mutation that causes the code to stop the production of the protein chain earlier than it is supposed to

2. "Frameshift Mutations"

   1. "Insertions" – a letter of DNA inserted inappropriately into the DNA code. DNA “words” are all 3 letters long, so adding a letter results in many words shifting; hence the name “frameshift mutation”.

   2. "Deletions" – a letter of DNA inappropriately removed from the DNA code. DNA “words” are all 3 letters long, so removing a letter results in many words shifting; hence the name “frameshift mutation”.

3. "Rearrangements"

   1. Sections of DNA can become mixed up, disrupting certain proteins and their functions